3-thioheteroaryl cephalosporin compounds, compositions and methods of use

ABSTRACT

Cephalosporin compounds of the formula I ##STR1## are disclosed. The compounds are useful against MRSA/MRCNS. Compositions and methods of use are also included.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application No. 08/277,731,filed on Jul. 20, 1994, now U.S. Pat. No. 5,498,777, priority of whichis claimed hereunder.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of thecephalosporin class in which the six membered ring of the cephalosporinnucleus is substituted with a thioheteroaryl group at position three.

Cephoxitin was an early cephalosporin antibacterial agent having a broadspectrum; it has the following formula: ##STR2##

The cephalosporins of the present invention have activity against grampositive and gram negative microorganisms, and are useful againstmethicillin resistant Staphylococcus aureus (MRSA), methicillinresistant Staphylococcus epidermidis (MRSE), and methicillin resistantcoagulase negative Staphylococci (MRCNS). The antibacterial compounds ofthe present invention thus comprise an important contribution to therapyfor these difficult to control pathogens.

Moreover, there is an increasing need for agents effective against suchpathogens (MRSA/MRCNS) which are at the same time safe, i.e., relativelyfree from undesirable side effects.

SUMMARY OF THE INVENTION

The present invention addresses a compound represented by formula I:##STR3## or a pharmaceutically acceptable salt or solvate thereof.

Y' represents CH or N.

M represents hydrogen, a negative charge, a biolabile ester forminggroup or a carboxyl protecting group.

R¹³ represents R¹ or N(R¹)₂.

W⁻ is present or absent, and when present, represents a negativelycharged counterion.

Z' represents (a) CR^(y') R^(z') wherein R^(y') and R^(z') independentlyrepresent H, C₁₋₆ alkyl or C₃₋₈ cycloalkyl, each optionally substitutedwith 1-3 groups selected from R^(e'), or (b) N substituted with OR¹ withR¹ equal to H, C₁₋₆ alkyl, C₁₋₆ alkyl substituted with from 1-3 groupsselected from R^(e') ; C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl, C₃₋₈cycloalkyl substituted with 1-3 groups selected from R^(e'), or C₃₋₈cycloalkenyl substituted with from 1-3 groups selected from R^(e').

R^(e') represents a member selected from the group consisting of:

a) --CF₃ ;

b) a halogen atom selected from the group consisting of --Br, --Cl, --Fand --I;

c) --OC₁₋₄ alkyl, wherein the alkyl portion thereof is optionallysubstituted by 1-3 groups selected from R^(q). R^(q) is selected fromthe group consisting of hydroxy, methoxy, cyano, --C(O)NH₂, --C(O)NHC₁₋₄alkyl, --C(O)N(C₁₋₄ alkyl)₂, --OC(O)NH₂, --CHO, --OC(O)NHC₁₋₄ alkyl,--OC(O)N(C₁₋₄ alkyl)₂, --SO₂ NH₂, --SO₂ N(C₁₋₄ alkyl)₂, --S(O)C₁₋₄alkyl, --SO₂ C₁₋₄ alkyl, --F, --CF₃, --SO₃ M^(b) with M^(b) representingH or an alkali metal, and --CO₂ M^(a),

where M^(a) is H, alkali metal, methyl or phenyl; tetrazolyl (where thepoint of attachment is the carbon atom of the tetrazole ring and one ofthe nitrogen atoms is optionally substituted by 1-3 of the other R^(q)groups as defined above);

d) --OH;

e) --OC(O)R^(s), where R^(s) is C₁₋₄ alkyl or phenyl, each of which isoptionally substituted by 1-3 groups R^(q) as defined above;

f) --OC(O)N(R^(y"))R^(z"), where R^(y") and R^(z") are independently H,C₁₋₄ alkyl, (optionally substituted by 1-3 R^(q) groups as definedabove), or are taken together to represent a 3- to 5-membered alkylideneradical which forms a ring (optionally substituted with R^(q) as definedabove), or a 2- to 4-membered alkylidene radical interrupted by --O--,--S--, --S(O)--or --S(O)₂ -- which forms a ring, said ring beingoptionally substituted with 1-3 groups R^(q) as defined above;

g) --S(O)_(n) --R^(s), where n=0-2, and R^(s) is defined above;

h) --SO₂ N(R^(y"))R^(z"), where R^(y") and R^(z") are as defined above;

i) --N₃ ;

j) --NR^(x).sub.(0-1) R^(y) R^(z) wherein R^(x), R^(y) and R^(z)independently represent H, C₁₋₄ alkyl or C₁₋₄ alkyl substituted withfrom 1-3 R^(q) groups, or R^(x), R^(y) and R^(z) are taken together torepresent either a 3- to 7-membered heterocyclic or heteroaryl ring,optionally substituted with 1-3 R^(q) groups, or a 2- to 4- memberedalkylidene radical interrupted by N, O or S(O)_(x) with x equal to 0, 1or 2, to form a ring, said alkylidene being optionally substituted withfrom 1 to 3 R^(q) groups,

such that when R^(x), R^(y) and R^(z) are present, NR^(x) R^(y) R^(z) isa quarterly nitrogen containing group which may be part of a ring;

or R^(x), R^(y) and R^(z) are taken in combination to represent a C₄ toC₁₀ alkanetriyl group, optionally substituted with 1-3 R^(q) groups,said alkanetriyl group being optionally interrupted with 1-3 heteroatomsselected from N⁺ R^(t), O and S(O)_(x) with x and R^(e') as definedabove;

k) --N(R^(t))C(O)H, where R^(t) is H or C₁₋₄ alkyl, said alkyl groupbeing optionally substituted with 1-3 groups R^(q) as defined above;

l) --N(R^(t))C(O)C₁₋₄ alkyl, wherein R^(t) is as defined above;

m) --N(R^(t))C(O)OC₁₋₄ alkyl, where R^(t) is as defined above;

n) --N(R^(t))C(O)N(R^(y))R^(z) where R^(t), R^(y) and R^(z) are definedabove;

o) --N(R^(t))SO₂ R^(s), where R^(s) and R^(t) are as defined above;

p) --CN;

q) a formyl or acetalized formyl radical which is --C(O)H or --CH(OCH₃)₂;

r) --C(OCH₃)₂ C₁₋₄ alkyl, where the alkyl is optionally substituted by1-3 groups R^(q) as defined above;

s) --C(O)R^(s), where R^(s) is as defined above;

t) --(C═NOR^(z"))R^(y") where R^(y") and R^(z") are as defined above,except they may not be joined together to form a ring;

u) --C(O)OC₁₋₄ alkyl, where the alkyl is optionally substituted by 1-3groups R^(q) as defined above:

v) --C(O)N(R^(y"))R^(z"), where R^(y") and R^(z") are as defined above;

w) --C(O)N(OR^(y"))R^(z"), where R^(y") and R^(z") are as defined above,except they may not be joined together to form a ring;

x) --C(S)N(R^(y"))R^(z") where R^(y") and R^(z") are as defined above;

y) --COOM^(a) where M^(a) represents H, C₁₋₄ alkyl, phenyl or an alkalimetal;

z) --SCN;

aa) --SCF₃ ;

ab) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is substituted by hydrogen,an alkali metal or a C₁₋₄ alkyl optionally substituted by R^(q) asdefined above:

ac) an anionic function which is selected from the group consisting of:P═O(OM^(a))₂ ; P═O(OM^(a))--[O(C₁₋₄ alkyl)]; P═O(OM^(a))--(C₁₋₄ alkyl);P═O(OM^(a))N(R^(y"))R^(z") ; P═O(OM^(a))NHR^(x') ; SO₂ M^(a) ; SO₃ M^(a); SO₂ NM^(a) CON(R^(y"))R^(z"), and SO₂ NM^(a) CN, where R^(x') isphenyl or heteroaryl, said heteroaryl group being a monocyclic, aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, one of the carbon atoms has been replaced by anitrogen atom, one carbon atom is optionally replaced by a heteroatomselected from O or S, and from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms, and where the phenyl andheteroaryl are optionally substituted by 1-3 groups R^(q), said R^(q),M^(a), R^(y") and R^(z") are as defined above;

ad) a C₃₋₇ cycloalkyl group;

ae) a C₅₋₇ cycloalkyl group in which one of the carbon atoms in the ringis replaced by a heteroatom selected from O, S, NH, or N(C₁₋₄ alkyl) andin which one additional carbon may be replaced by the NH or N(C₁₋₄alkyl), and in which at least one carbon atom adjacent to each nitrogenheteroatom has both of its attached hydrogen atoms replaced by oneoxygen thus forming a carbonyl moiety and there are one or two carbonylmoieties present in the ring;

af) a C₂₋₄ alkenyl radical, optionally substituted by 1-3 of thesubstituents a) to ac) above and phenyl which is optionally substitutedby R^(q) as defined above;

ag) a C₂₋₄ alkynyl radical, optionally substituted by 1-3 of thesubstituents a) to ac) above;

ah) a C₁₋₄ alkyl radical;

ai) a C₁₋₄ alkyl group substituted by 1-3 of the substituents a)-aa)above;

aj) a C₁₋₄ alkyl radical substituted with 1-3 groups selected from aryl,oxime, heteroaryl, C₃₋₇ cycloalkyl and heterocycloalkyl, each of whichis unsubstituted or substituted with 1 to 3 R^(q) groups;

ak) a C₃₋₇ cycloalkyl radical substituted with 1-3 of the substituentsa)-aa) above;

al) a C₃₋₇ heterocycloalkyl radical substituted with 1-3 of thesubstituents a)-aa) above:

am) a C₆₋₁₀ aryl radical;

an) a C₆₋₁₀ aryl radical substituted with 1-3 of the substituents a)-aa)above;

ao) a 6-10 membered heteroaryl radical; and

ap) a 6-10 membered heteroaryl radical substituted with 1-3 of thesubstituents a)-aa) above. ##STR4## represents a heterocyclic group withfrom one to three positively charged atoms, and is selected from thegroup consisting of: ##STR5## represents the point of attachment to S;

A, B, C, D, X and Y independently represent C or N;

Z represents C, O, S or N, such that at least one of A, B, C, D, X and Yrepresents N, or Z represents O, S or N.

one R^(e) represents -R* and the others represent H, R^(e') or R^(f).

--R* represents one of the groups (a) through (c): ##STR6##

and (c) --E_(p) --N⁺ R¹⁰ R¹¹ R¹².sub.(0-1).

When --R* represents ##STR7##

E represents --(CR³ R⁴)_(r) --Q--(CR³ R⁴)_(s) -- wherein r is 0-6, s is1-6;

Q represents a member selected from the group consisting of: a covalentbond, --O--, --S(O)_(x) -- with x equal to 0, 1 or 2, --NR³ --, --SO₂NR³ --, --NR³ SO₂ --, --C(O)NR³ --, --NR³ C(O)--, --CR³ ═CR⁴ --,--C(O)--, --OC(O)--, --(O)CO--, ##STR8## with R³ and R⁴ independentlyrepresent H or C₁₋₄ lower alkyl, and (CR³ R⁴)_(s) -- being attached tothe ring nitrogen. ##STR9## represents a 5 or 6 membered monocyclicheterocycle or an 8-10 membered bicyclic heterocycle, bonded to Ethrough the ring nitrogen and having a substituent group R^(f)optionally attached to the ring nitrogen, and having 0-3 R^(e') groupsattached to other atoms of the heterocyclic group, said ring nitrogenbeing tertiary or quarternary by virtue of E, the ring bonds and theoptional R^(f) which may be attached, said heterocyclic group beingaromatic, partially aromatic or non-aromatic.

The heterocycle also contains 0-3 additional nitrogen atoms and 0-1oxygen or sulfur atom.

Each R^(f) independently represents hydrogen, --NH₂, --O⁻, --C₁₋₄ alkyl,optionally substituted with 1-3 groups selected from R^(q) ; --C₃₋₇cycloalkyl, optionally substituted with 1-3 groups selected from R^(q) ;--C₅₋₇ cycloalkyl group in which one of the carbon atoms in the ring isreplaced by a heteroatom selected from O, S, NH, or N(C₁₋₄ alkyl) and inwhich one additional carbon may be replaced by the NH or N(C₁₋₄ alkyl),and in which at least one carbon atom adjacent to each nitrogenheteroatom has both of its attached hydrogen atoms replaced by oneoxygen thus forming a carbonyl moiety and there are one or two carbonylmoieties present in the ring; a C₂₋₄ alkenyl radical, optionallysubstituted by 1-3 substituents R^(q) ; a C₂₋₄ alkynyl radical,optionally substituted by 1-3 substituents selected from R^(q) ; a C₁₋₄alkyl radical substituted with 1-3 groups selected from aryl, oxime,heteroaryl, C₃₋₇ cycloalkyl and heterocycloalkyl, each of which isunsubstituted or substituted with 1 to 3 groups selected from R^(q) ; aC₃₋₇ cycloalkyl radical optionally substituted with 1-3 substituentsselected from R^(q) ; a C₆₋₁₀ aryl radical, optionally substituted with1-3 substituents selected from R^(q) ; and a 6-10 membered heteroarylgroup, optionally substituted with 1-3 substituents selected from R^(q).

When --R* represents ##STR10##

E' represents --(CR³ R⁴)_(m) '--Q--(CR³ R⁴)_(m) '-- with each m'independently equal to 0-6, and Q, R³ and R⁴ as defined above, exceptthat when each m' is 0, Q is not a covalent bond, and --(CF³ R⁴)_(m) 'attached to the heterocyclic ring. ##STR11## represents a 5 or 6membered monocyclic heterocycle or an 8-10 membered bicyclicheterocycle, said heterocycle being aromatic, partially aromatic ornon-aromatic, bonded to E' through an atom other than the ring nitrogen,and having 0-2 R^(f) groups attached to the ring nitrogen, said nitrogenin the heterocycle being tertiary or quaternary by virtue of the ringbonds and the optional R^(f) groups which may be attached.

The heterocycle further contains 0-1 oxygen or sulfur atom and 0-2additional nitrogen atoms therein.

R^(e') and R^(f) are as defined above.

When --R* represents

(c) --E_(p) --N+R¹⁰ R¹¹ R¹² (0-1),

E is as defined above and p is an integer 0 or 1.

R¹⁰, R¹¹ and when present, R¹², are independently H, C₁₋₄ alkyl or C₁₋₄alkyl substituted with 1-3 R^(q) groups, such that when R¹² is present,the N is quaternary, and when R¹² is absent, the N is tertiary;

or R¹⁰ and R¹¹ are taken together to represent a C₃₋₇ alkylidene radicalto form a ring (optionally substituted with 1-3 R^(q) groups as definedbelow), uninterrupted or interrupted by O, S, S(O), SO₂, N(O)R^(e') orN+(R^(e'))₁₋₂ (where R^(e') is as previously defined),

or R¹⁰, R¹¹ and R¹² are taken in combination to represent a C₄ to C₁₀alkanetriyl group, optionally substituted with 1-3 R^(e') groups, saidalkanetriyl group being optionally interrupted with 1-3 heteroatomsselected from N+R^(e'), O and S(O)_(x) with x and R^(e') as definedabove.

Also included are pharmaceutical compositions which are comprised of acompound of formula I in combination with a pharmaceutically acceptablecarrier.

Also included are methods of use which are comprised of administering toa mammal in need of such treatment a compound in accordance with formulaI in an amount effective to treat a bacterial infection.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

Carboxylic acid refers to --COOH.

Carboxylate anion refers to a negatively charged group --COO--.

An N-hydroxycarbamoyl or N(C₁₋₄ alkoxy)carbamoyl radical in which thenitrogen atom may be additionally substituted by a C₁₋₄ alkyl group is:--C(O)N(OR^(y"))R^(z"), where R^(y") and R^(z") are as defined, exceptthey may not be joined together to form a ring.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 10 carbon atoms unless otherwise defined.It may be straight, branched or cyclic. Preferred alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl andcyclohexyl. When substituted, alkyl groups may be substituted with up tofour substituent groups, at any available point of attachment. When thealkyl group is said to be substituted with an alkyl group, this is usedinterchangeably with "branched alkyl group".

The term "alkoxy" refers to a C₁₋₄ alkoxy radical: --OC₁₋₄ alkyl,wherein the alkyl is optionally substituted by 1-3 groups selected fromR^(q). R^(q) is selected from hydroxy, methoxy, cyano, --C(O)NH₂,--C(O)NHC₁₋₄ alkyl, --C(O)N(C₁₋₄ alkyl)₂, --OC(O)NH₂, --CHO,--OC(O)NHC₁₋₄ alkyl, --OC(O)N(C₁₋₄ alkyl)₂, --SO₂ NH₂, --SO₂ N(C₁₋₄alkyl)₂, --S(O)C₁₋₄ alkyl, --SO₂ C₁₋₄ alkyl, --F, --CF₃, --SO₃ M^(b)(with M^(b) representing H or an alkali metal), and --CO₂ M^(a) (whereM^(a) is H, alkali metal, methyl or phenyl); tetrazolyl (where the pointof attachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is optionally substituted by 1-3 R^(q) groups as definedabove). The preferred alkoxy group is methoxy.

A hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁₋₄ alkyl group is the group:--C═N(OR^(z"))R^(Y") where R^(z") represents a C₁₋₄ alkyl group andR^(y") is as previously defined, except they may not be joined togetherto form a ring.

The term "oxime" and "hydroxyimino" can be used interchangeably to referto the group: ═N--OH. When the oxime is substituted on the hydroxylportion thereof, this is represented by the structure: ═N--OR^(z").

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms,without alternating or resonating double bonds between carbon atoms. Itmay contain from 1 to 4 rings which are fused. The preferred cycloalkylgroups are cyclopentyl and cyclohexyl.

The term "alkenyl" refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 10 carbon atoms and at least one carbon tocarbon double bond. Preferred alkenyl groups include ethenyl, propenyl,butenyl and cyclohexenyl.

Cycloalkenyl is a subset of alkenyl, containing from 5 to 10 carbonatoms, in one or two fused rings, with at least one carbon to carbondouble bond.

The term "alkynyl" refers to a hydrocarbon radical straight or branched,containing from 2 to 10 carbon atoms and at least one carbon to carbontriple bond. Preferred alkynyl groups include ethynyl, propynyl andbutynyl.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and thelike, groups as well as rings which are fused, e.g., naphthyl,phenanthrenyl and the like. An aryl group thus contains at least onering having at least 6 atoms, with up to five such rings being present,containing up to 22 atoms therein, with alternating (resonating) doublebonds between adjacent carbon atoms or suitable heteroatoms. Thepreferred aryl groups are phenyl, naphthyl and phenanthrenyl. Arylgroups may be substituted as defined. Preferred substituted arylsinclude phenyl and naphthyl.

The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10atoms, containing at least one heteroatom, O, S or N, in which a carbonor nitrogen atom is the point of attachment, and in which one or twoadditional carbon atoms are optionally replaced by a heteroatom selectedfrom O or S, and in which from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms, said heteroaryl group beingoptionally substituted as described herein.

Heteroaryl thus includes aromatic and partially aromatic groups whichcontain one or more heteroatoms. Examples of this type are pyrrole,pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms maybe present together with the first nitrogen and oxygen or sulfur,giving, e.g., thiadiazole. Preferred heteroaryl groups are thiazolyl,imidazolyl, pyridyl and pyrrolyl.

Heteroarylium groups are those heteroaryls which contain one or morequaternary nitrogen atoms.

The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic)in which one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S or N, and in which up to three additional carbonatoms may be replaced by said heteroatoms. Preferred heterocycloalkylgroups include piperidinyl, pyrrolidinyl and tetrahydrofuranyl. The Natoms of said heterocycloalkyl groups may be tertiary or quaternary.

The term "quaternary nitrogen" refers to a tetravalent positivelycharged nitrogen atom including, e.g., the positively charged nitrogenin a tetraalkylammonium group (e.g.. tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in protonatedammonium species (e.g. trimethylhydroamrnonium, N-hydropyridinium), thepositively charged nitrogen in amine N-oxides (e.g..N-methylmorpholine--N-oxide, pyridine-N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g.. N-aminopyridinium).

In --R*, when the --R * represents (a), and there is no --R^(f) grouppresent on the nitrogen atom which is shown, the nitrogen is quaternarywhen the ring containing said nitrogen is aromatic, by virtue of thering bonds and bond to E'. Likewise, when R^(f) is absent and the ringbonds and bond to E provide for 3 bonds to the nitrogen atom, thenitrogen is tertiary and not positively charged.

In --R*, when the --R* represents (b), and there is one --R^(f) grouppresent on the nitrogen atom which is shown, the nitrogen is quaternarywhen the ring containing said nitrogen is aromatic, by virtue of thering bonds and the bond to R^(f). Likewise, when R^(f) is absent and thering is aromatic, the nitrogen is tertiary and not positively charged.When the ring is non-aromatic and one R^(f) is attached, the nitrogen isnon-quaternary. When the ring is nonaromatic and two R^(f) groups areattached, the ring nitrogen atom shown is quaternary.

The term "heteroatom" means O, S or N, selected on an independent basis.

Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.

The term "alkali metal" refers to species which may be positivelycharged, such as, for example, Na, K, Ca, Mg and the like.

When a group is termed "substituted", unless otherwise indicated, thismeans that the group contains from 1 to 4 substituents thereon at anyavailable point of attachment.

When a functional group is termed "protected", this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al. Protective Groups inOrganic Synthesis Wiley, New York (1991 ). Examples of suitableprotecting groups are contained throughout the specification.

In the preparation methods described herein, the carboxyl group at the4-position typically remains blocked until the ultimate or penultimatestep, when the final product is prepared. These blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with fluoride ion, treatment with atransition metal catalyst and a nucleophile and catalytic hydrogenation.

Examples of suitable hydroxyl protecting groups which can be used in thesyntheses described herein are: t-butylmethoxyphenylsilyl,t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl,o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl andallyloxycarbonyl. Preferred hydroxyl protecting groups aretrimethylsilyl and triethylsilyl.

Examples of suitable carboxyl protecting groups are: benzhydryl,o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl,benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl,p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl.Preferred carboxyl protecting groups include p-nitrobenzyl andp-methoxybenzyl.

In any given structure, where a variable appears more than once, each isto be determined on an independent basis. For example, in thestructures: ##STR12## each X, Y and Z is determined independently. BothX's can represent N or C, or one can represent N while the otherrepresents C. Also, each R^(e) group is determined independently.

The HET group is aromatic and contains at least one heteroatom. Hence,for any given alternative ring system, at least one of A, B, C, D, X, Yand Z is a heteroatom. When a variable appears twice, they can be thesame or different. Because HET is aromatic, alternating double bonds aredrawn. Z is drawn with 2 bonds attached; however, Z may also have 3-4bonds when appropriate, when Z is N or C.

The compounds of the present invention are useful in variouspharmaceutically acceptable salt forms for the treatment of bacterialinfections in animal and human subjects. The term "pharmaceuticallyacceptable salt" refers to those salt forms which would be apparent tothe pharmaceutical chemist. i.e., those which are substantiallynon-toxic and which provide the desired pharmacokinetic properties,palatability, absorption, distribution, metabolism or excretion. Otherfactors, more practical in nature, which are also important in theselection, are cost of the raw materials, ease of crystallization,yield, stability, hygroscopicity, and flowability of the resulting bulkdrug. Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers. Thus, the present invention is concerned with pharmaceuticalcompositions and methods of treating bacterial infections utilizing thecompound of formula I.

The compounds of the invention are electronically balanced. Hence thecompounds of formula I are ordinarily present in association with anappropriately charged counterion or counterions. Since a bis-quaternaryammonium group is present in many of the compounds of the invention, oneor two negatively charged counterions are also present to provideoverall electronic balance. The other counterion, termed generically W⁻,can vary widely, depending upon the particular counterion desired. Inthe final compound, a single positive charge in the HET group can bebalanced by a negatively charged counterion or the negatively chargedcarboxylate, CO₂ --, which is attached to the cephalosporin nucleus atposition 3. When more than one positive charge is present, a negativelycharged counterion is present as well. The counterion W⁻ is apharmaceutically acceptable anionic species and may vary widely. Thedesired counterion W⁻ may be introduced by standard techniques asdescribed above, such as by conducting an ion exchange. It is understoodthat when the counterion W⁻ is an anionic species possessing more thanone negative charge, then an appropriate amount of W⁻ is present toresult in overall electronic balance with the final compound I. When W⁻is dianionic, one-half of a molar equivalent of W⁻ is present relativeto the net positively charged cephalosporin moiety. The pharmaceuticallyacceptable salt forms of the compounds of formula I mentioned aboverefer to the various possibilities for the charge balancing counterionW⁻. Anions derived from inorganic and organic acids are suitable.Representative examples of such counterions are the following: acetate,adipate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate,benzoate, benzenesulfonate, bisulfate, bromide, citrate, camphorate,camphorsulfonate, chloride, digluconate, edetate, edisylate, estolate,ethanesulfonate, fumarate, glucoheptanoate, gluconate, glutamate,glycerophosphate, glycolate, hydroxynaphthoate,2-hydroxyethanesulfonate, iodide, lactate, lactobionate, malate,maleate, mandelate, methylenebis(salicylate), mucate, methanesulfonate,napadisylate, napsylate, pamoate, pantothenate, pectinate,phosphate/diphosphate, polygalacturonate, propionate, salicylate,stearate, succinate, sulfate, tartrate, tosylate and undecanoate. Otheranionic species will be apparent to the ordinarily skilled chemist.

One subset of compounds of the present invention includes thosecompounds where Y' represents N.

Another subset of compounds are those in which HET represents: ##STR13##In these compounds, X is preferably a nitrogen atom. The preferredvalues of A, B, C and D are carbon, thus forming a fused benzene ring,or 1-2 of the variables represent a nitrogen atom, thus forming a fusedpyridine, pyrimidine or pyrazine ring. Suitable examples of these ringsystems include the following: ##STR14##

Another subset of compounds of the invention are those in which X isnitrogen and Z represents a sulfur atom. Examples of this ring systeminclude the following: ##STR15##

Another subset of compounds are those in which HET represents: ##STR16##In these compounds, X is preferably a nitrogen atom. A subset ofcompounds of the invention includes those in which X is nitrogen and Zrepresents a sulfur atom. Illustrative of this ring system are thefollowing: ##STR17##

In the compounds of the present invention, one of the R^(e) groupsrepresents --R*. One subset of--R* is of type (a). Illustrative of thisquaternary ring system are the following: ##STR18##

For the structures above, where R^(e') is shown to have an indefiniteposition, it is attached to any available atom of the ring. Where tworings are shown and more than 3 R^(e') groups are shown attached, thismeans that up to 3 may be included at available points of attachment.

Another subset of compounds includes those compounds where --R* is oftype (b): ##STR19##

In this subtype, E' is attached to an atom of the aromatic ring otherthan a nitrogen atom. Illustrative of this subtype are the following:##STR20##

Another subset of compounds of the present invention includes compoundswhere --R* is of type (c):

    --E.sub.p --N.sup.+ R.sup.10 R.sup.11 R.sup.12.sub.(0-1).

Illustrative of this particular subtype are the following:

    --Ep--N.sup.+ (CH.sub.3).sub.3, --Ep--N.sup.+ (CH.sub.2 CH.sub.3).sub.3, --Ep--N.sup.+ (CH.sub.3).sub.2 CH.sub.2 R.sup.q --Ep--N.sup.+ (CH.sub.2 CH.sub.3).sub.2 CH.sub.2 CH.sub.2 R .sup.q, ##STR21## where W is O, S, NH, NR.sup.3', N(O)R.sup.e', SO, SO.sub.2, NH.sub.2.sup.+, NHR.sup.e'+, or N.sup.+ (R.sup.e').sub.2 and W' is NH.sup.+, N.sup.+ R.sup.e' or NO. Where R.sup.e' is shown to have an indefinite position, it may be attached to any available atom of the ring.

Examples of specific compounds falling within the scope of the presentinvention include those set forth in tables I-III below.

                                      TABLE I                                     __________________________________________________________________________     ##STR22##                                                                     ##STR23##                                                                                  ##STR24##                                                       __________________________________________________________________________    1 CH.sub.3                                                                                  ##STR25##                                                       2 CH.sub.3                                                                                  ##STR26##                                                       3 CH.sub.2 CH.sub.2 F                                                                       ##STR27##                                                       4 CH.sub.2 CH.sub.2 F                                                                       ##STR28##                                                       5 CH.sub.2 CH.sub.2 F                                                                       ##STR29##                                                       6 CH.sub.2 CH.sub.2 F                                                                       ##STR30##                                                       7 CH.sub.2 CH.sub.2 F                                                                       ##STR31##                                                       8 CH.sub.2 CH.sub.2 F                                                                       ##STR32##                                                       9 CH.sub.2 CH.sub.2 F                                                                       ##STR33##                                                       10                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR34##                                                       11                                                                              CH.sub.2 CH.sub.2 Br                                                                      ##STR35##                                                       12                                                                              CH.sub.2 CH.sub.2 Br                                                                      ##STR36##                                                       13                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR37##                                                       14                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR38##                                                       15                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR39##                                                       16                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR40##                                                       17                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR41##                                                       18                                                                              CH.sub.2 CH.sub.2 Cl                                                                      ##STR42##                                                       19                                                                              CH.sub.2 CH.sub.2 Cl                                                                      ##STR43##                                                       20                                                                              CH.sub.2 CH.sub.2 Cl                                                                      ##STR44##                                                       21                                                                              CH.sub.2 F                                                                                ##STR45##                                                       22                                                                              CH.sub.2 F                                                                                ##STR46##                                                       23                                                                              CH.sub.2 CF.sub.3                                                                         ##STR47##                                                       24                                                                              CH.sub.2 CF.sub.3                                                                         ##STR48##                                                       25                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                                ##STR49##                                                       26                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                                ##STR50##                                                       27                                                                              CH.sub.2 CHCCl.sub.2                                                                      ##STR51##                                                       28                                                                              CH.sub.2 CHCCl.sub.2                                                                      ##STR52##                                                       29                                                                              CH.sub.2 CH.sub.2 OH                                                                      ##STR53##                                                       30                                                                              CH.sub.2 CH.sub.2 OH                                                                      ##STR54##                                                       31                                                                              CH.sub.2 SCH.sub.3                                                                        ##STR55##                                                       32                                                                              CH.sub.2 SCH.sub.3                                                                        ##STR56##                                                       33                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR57##                                                       34                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR58##                                                       35                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR59##                                                       36                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR60##                                                       37                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR61##                                                       38                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR62##                                                       39                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR63##                                                       40                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR64##                                                       41                                                                              CH.sub.2 CH(CH.sub.3).sub.2                                                               ##STR65##                                                       42                                                                              CH.sub.2 CH(CH.sub.3).sub.2                                                               ##STR66##                                                       43                                                                              CH(CH.sub.3).sub.3                                                                        ##STR67##                                                       44                                                                              CH(CH.sub.3).sub.3                                                                        ##STR68##                                                       45                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                  ##STR69##                                                       46                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                  ##STR70##                                                       47                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                  ##STR71##                                                       48                                                                              H                                                                                         ##STR72##                                                       49                                                                              H                                                                                         ##STR73##                                                       50                                                                              H                                                                                         ##STR74##                                                       51                                                                               ##STR75##                                                                                ##STR76##                                                       52                                                                               ##STR77##                                                                                ##STR78##                                                       53                                                                               ##STR79##                                                                                ##STR80##                                                       54                                                                               ##STR81##                                                                                ##STR82##                                                       55                                                                              H                                                                                         ##STR83##                                                       56                                                                              H                                                                                         ##STR84##                                                       57                                                                              H                                                                                         ##STR85##                                                       58                                                                               ##STR86##                                                                                ##STR87##                                                       59                                                                               ##STR88##                                                                                ##STR89##                                                       60                                                                               ##STR90##                                                                                ##STR91##                                                       61                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR92##                                                       62                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR93##                                                       63                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR94##                                                       64                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR95##                                                       65                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR96##                                                       66                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR97##                                                       67                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR98##                                                       68                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR99##                                                       69                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR100##                                                      70                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR101##                                                      71                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR102##                                                      72                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR103##                                                      73                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR104##                                                      74                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR105##                                                      75                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR106##                                                      76                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR107##                                                      77                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR108##                                                      78                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR109##                                                      79                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR110##                                                      80                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR111##                                                      __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR112##                                                                    ##STR113##                                                                                 ##STR114##                                                      __________________________________________________________________________    1 CH.sub.3                                                                                  ##STR115##                                                      2 CH.sub.3                                                                                  ##STR116##                                                      3 CH.sub.2 CH.sub.2 F                                                                       ##STR117##                                                      4 CH.sub.2 CH.sub.2 F                                                                       ##STR118##                                                      5 CH.sub.2 CH.sub.2 F                                                                       ##STR119##                                                      6 CH.sub.2 CH.sub.2 F                                                                       ##STR120##                                                      7 CH.sub.2 CH.sub.2 F                                                                       ##STR121##                                                      8 CH.sub.2 CH.sub.2 F                                                                       ##STR122##                                                      9 CH.sub.2 CH.sub.2 F                                                                       ##STR123##                                                      10                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR124##                                                      11                                                                              CH.sub.2 CH.sub.2 Br                                                                      ##STR125##                                                      12                                                                              CH.sub.2 CH.sub.2 Br                                                                      ##STR126##                                                      13                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR127##                                                      14                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR128##                                                      15                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR129##                                                      16                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR130##                                                      17                                                                              CH.sub.2 CH.sub.2 I                                                                       ##STR131##                                                      18                                                                              CH.sub.2 CH.sub.2 Cl                                                                      ##STR132##                                                      19                                                                              CH.sub.2 CH.sub.2 Cl                                                                      ##STR133##                                                      20                                                                              CH.sub.2 CH.sub.2 Cl                                                                      ##STR134##                                                      21                                                                              CH.sub.2 F                                                                                ##STR135##                                                      22                                                                              CH.sub.2 F                                                                                ##STR136##                                                      23                                                                              CH.sub.2 CF.sub.3                                                                         ##STR137##                                                      24                                                                              CH.sub.2 CF.sub.3                                                                         ##STR138##                                                      25                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                                ##STR139##                                                      26                                                                              CH.sub.2 CH.sub.2 CH.sub.3                                                                ##STR140##                                                      27                                                                              CH.sub.2 CHCCl.sub.2                                                                      ##STR141##                                                      28                                                                              CH.sub.2 CHCCl.sub.2                                                                      ##STR142##                                                      29                                                                              CH.sub.2 CH.sub.2 OH                                                                      ##STR143##                                                      30                                                                              CH.sub.2 CH.sub.2 OH                                                                      ##STR144##                                                      31                                                                              CH.sub.2 SCH.sub.3                                                                        ##STR145##                                                      32                                                                              CH.sub.2 SCH.sub.3                                                                        ##STR146##                                                      33                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR147##                                                      34                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR148##                                                      35                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR149##                                                      36                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR150##                                                      37                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR151##                                                      38                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR152##                                                      39                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR153##                                                      40                                                                              CH.sub.2 CH.sub.2 CH.sub.2 F                                                              ##STR154##                                                      41                                                                              CH.sub.2 CH(CH.sub.3).sub.2                                                               ##STR155##                                                      42                                                                              CH.sub.2 CH(CH.sub.3).sub.2                                                               ##STR156##                                                      43                                                                              CH(CH.sub.3).sub.3                                                                        ##STR157##                                                      44                                                                              CH(CH.sub.3).sub.3                                                                        ##STR158##                                                      45                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                  ##STR159##                                                      46                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                  ##STR160##                                                      47                                                                              CH.sub.2 C.sub.6 H.sub.5                                                                  ##STR161##                                                      48                                                                              H                                                                                         ##STR162##                                                      49                                                                              H                                                                                         ##STR163##                                                      50                                                                              H                                                                                         ##STR164##                                                      51                                                                               ##STR165##                                                                               ##STR166##                                                      52                                                                               ##STR167##                                                                               ##STR168##                                                      53                                                                               ##STR169##                                                                               ##STR170##                                                      54                                                                               ##STR171##                                                                               ##STR172##                                                      55                                                                              H                                                                                         ##STR173##                                                      56                                                                              H                                                                                         ##STR174##                                                      57                                                                              H                                                                                         ##STR175##                                                      58                                                                               ##STR176##                                                                               ##STR177##                                                      59                                                                               ##STR178##                                                                               ##STR179##                                                      60                                                                               ##STR180##                                                                               ##STR181##                                                      61                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR182##                                                      62                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR183##                                                      63                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR184##                                                      64                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR185##                                                      65                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR186##                                                      66                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR187##                                                      67                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR188##                                                      68                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR189##                                                      69                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR190##                                                      70                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR191##                                                      71                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR192##                                                      72                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR193##                                                      73                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR194##                                                      74                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR195##                                                      75                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR196##                                                      76                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR197##                                                      77                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR198##                                                      78                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR199##                                                      79                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR200##                                                      80                                                                              CH.sub.2 CH.sub.2 F                                                                       ##STR201##                                                      __________________________________________________________________________

                                      TABLE III                                   __________________________________________________________________________     ##STR202##                                                                    ##STR203##                                                                              ##STR204##                                                         __________________________________________________________________________    1 CH.sub.2 CH.sub.3                                                                      ##STR205##                                                         2 CH.sub.2 CH.sub.3                                                                      ##STR206##                                                         3 CH.sub.2 C(CH.sub.3).sub.3                                                             ##STR207##                                                         4 CH.sub.2 C(CH.sub.3).sub.3                                                             ##STR208##                                                            ##STR209##                                                                            ##STR210##                                                         6                                                                                ##STR211##                                                                            ##STR212##                                                         7                                                                                ##STR213##                                                                            ##STR214##                                                         8                                                                                ##STR215##                                                                            ##STR216##                                                         9                                                                                ##STR217##                                                                            ##STR218##                                                         10                                                                               ##STR219##                                                                            ##STR220##                                                         11                                                                              CH.sub.2 CH.sub.3                                                                      ##STR221##                                                         12                                                                              CH.sub.2 CH.sub.3                                                                      ##STR222##                                                         13                                                                              CH.sub.2 C(CH.sub.3).sub.3                                                             ##STR223##                                                         14                                                                              CH.sub.2 C(CH.sub.3).sub.3                                                             ##STR224##                                                         15                                                                               ##STR225##                                                                            ##STR226##                                                         16                                                                               ##STR227##                                                                            ##STR228##                                                         17                                                                               ##STR229##                                                                            ##STR230##                                                         18                                                                               ##STR231##                                                                            ##STR232##                                                         19                                                                               ##STR233##                                                                            ##STR234##                                                         20                                                                               ##STR235##                                                                            ##STR236##                                                         __________________________________________________________________________     ##STR237##

The synthesis of compounds of Formula I may be carried out as shown inreaction schemes A and B.

With reference to the reaction schemes: ##STR238## represents aheterocyclic moiety which is converted to the moiety ##STR239## offormula I.

P represents an acid labile nitrogen protecting group or hydrogen.

When R¹ in formula I is hydrogen R¹ in the scheme can be an acid labilehydroxy protecting group. ##STR240## represents a tertiary aromatic,heteroaromatic or aliphatic amine which by reaction with the cephemalkylating group results in a quaternary group of the present invention.

The starting material for the synthesis is the readily available3-hydroxycephem 1(M=p-methoxy benzyl or benzhydryl). As shown in schemeA, reaction of 1 with a suitable trifluoromethanesulfonyl source, suchas trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chlorideor the like, in the presence of an organic nitrogen base, such astriethylamine, diisopropyl amine and the like in an aprotic solvent suchas methylene chloride or tetrahydrofuran gives thetriflouromethanesulfonate at the 3-position, as a stable isolable solid2. Reaction of 2 with the sodium salt of a suitable heteroaryl thiol,prepared by the reaction of a reagent such as sodium hydride or sodiumhexamethyldisilazide with the thiol, in a non-polar solvent or solventmixture at -20° C. to room temperature, gives the desired additionproduct 4, as a mixture of the Δ² and Δ³ isomers. The desired Δ³ isomeris separated by fractional crystallization or by chromatography.

The heterocyclic thiol used herein is usually not the same as the finalsubstituent HET but bears a group that eventually can be converted toit.

The heterocyclic thiols used in the synthesis of the present inventionare, in many cases known in the literature and many are commerciallyavailable. In those cases where the required heterocyclic thiol isneither commercially available or known in the literature, they can beeasily prepared by one skilled in the art by modification of literaturesyntheses towards the desired heterocyclic thiol.

The phenylacetyl side chain at the 7-position is removed by procedureswell known in the art, such as reaction with phosphorous pentachloridein the presence of a base such as pyridine at -20° to -10° C. for 1hour, followed by reaction of the intermediate with methanol at -15° to-10° C. for 1.5 hours. This is followed by treatment with a phosphatebuffer at pH 2 for 0.5 hour at room temperature, to give the product 5,isolated as its p-toluensulfonic acid salt. In the case where theheteroaryl group of 4 has a hydroxymethyl group attached to it, theabove reaction results in simultaneous conversion of the hydroxymethylgroup to the chloromethyl group in 5. Alternatively the hydroxymethylgroup in 4 can be converted to the chloromethyl group by reaction with asuitable chlorinating agent such as thionyl chloride and pyridine orphosphorous oxychloride and pyridine before subjecting the compound tothe side chain removing reaction sequence described above.

The free amino group of 5 can be acylated with the desired acidchloride, prepared from the acid by reaction of the acid in-situ with anumber of reagents known in the art such as phosphorous oxychloride andpyridine or oxalyl chloride and dimethylformamide. Alternatively theacid may be reacted directly with the amine in the presence of acoupling reagent such as a carbodiimide to give the desired amide 6. Theamino function in the acid chloride is usually protected with an acidlabile protecting group.

In an alternate route shown in scheme B, the triflate 2 is treated withthe side chain removing sequence to give the triflate 10 which is thenreacted with the desired acid or its acid chloride to give the triflate11 which has the desired 7-side chain in place. Reaction of 11 with thesodium salt of the thiol then gives a compound such as 12, which bears ahydroxyalkyl substituent on the heteroaryl substituent. The hydroxygroup is converted to a leaving group such as a methanesulfonate ortrifluoromethanesulfonate by reaction with methane sulfonyl chloride ortrifluoromethane sulfonic anhydride in the presence of a base such astriethylamine or pyridine or 2,6-collidine to give 13.

Reaction of compound 6 or 13 with potassium iodide in acetone from about-10° C. to about room temperature gives the iodo derivative 7.

The introduction of the quaternary substituent is carried out bytreatment of the iodo compound 7 with the tertiary amine correspondingto the quaternary substituent. The alkylation of the tertiary amine bythe iodo compound 7 is carried out by reacting the two in an inert polarsolvent such as acetonitrile, DMF, N-methylpyrrolidinone, etc. in thepresence of the silver salt of a non-nucleophillic acid such as silvertrifluoromethanesulfonate, silver trifluoroborate and the like to givecompound 8. In certain cases when the leaving group istrifluoromethanesulfonate of 13, excess tertiary amine quaternizingagent can be used as both base and quaternizing agent.

The carboxylic acid protecting group M is then removed by treatment witha strong organic acid such as trifluoroacetic acid, in the presence of acarbonium ion acceptor such as anisole to give the free acid. Theprocedure also results in the concomitant removal of other acid labileprotecting groups in the molecule resulting in the final desired productof the invention 9.

The compound of the invention may be used in a variety of pharmaceuticalpreparations. Compositions for injection, the preferred route ofdelivery, may be prepared in unit dosage form in ampoules or inmultidose containers. The compositions may take such forms assuspensions, solutions or emulsions, oily or aqueous in nature, and maycontain various formulating agents, such as diluents, buffers,preservatives and the like. Hence, the compound is present incombination with these pharmaceutically acceptable carriers.

Alternatively, the active ingredient may be in the form of a powder,which can be reconstituted with a suitable carrier such as sterilewater, normal saline and the like at the time of administration. Thepowder can be in lyophilized or non-lyophillized form.

Oral compositions are typically in the form of tablets, capsules,solutions or suspensions. Such compositions may likewise be packaged inunit dose or multidose containers. In these oral compositions, thepharmaceutically acceptable carriers may be comprised of diluents,tableting and granulating aids, lubricants, disintegrants, buffers,sweeteners, preservatives and the like.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration. The parenteral route (by injection) ispreferred for generalized infections. Such matters, however, aretypically left to the discretion of the clinician according toprinciples of treatment well known in the antibacterial arts.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from about 0.01% to about 99% of active material, thepreferred range being from about 10-60%. The composition will generallycontain from about 15 mg to about 2000 mg of the active ingredient;however, in general, it is preferable to employ a dosage amount in therange of from about 250 mg to 1000 mg. In parenteral administration, theunit dosage is usually the compound I in a sterile water or salinesolution or in the form of a soluble powder intended for solution.

The preferred method of administration of the compound of formula I isparenterally by intravenous (i.v.) infusion. Alternatively, the compoundmay be administered intramuscularly (i.m.).

For adults, a dose of about 5 to about 50 mg of the formula Iantibacterial compound per kg of body weight is administered from 1 to 6times per day. The preferred dosage ranges from about 250 mg to 1000 mgof the compound given one to four times per day.

More specifically, for mild infections a dose of 250 mg two to fourtimes daily is preferred. For moderate infections against highlysusceptible gram positive organisms a dose of 500 mg b.i.d. to q.i.d. ispreferred. For severe, life-threatening infections against organisms atthe upper limits of sensitivity to the antibiotic, a dose of about1000-2000 mg two to six times daily is preferred.

For children, a dose of 5-25 mg/kg of body weight given 1 to 4 times perday is preferred; a dose of 10 mg/kg b.i.d., t.i.d. or q.i.d. isrecommended.

The compounds of the present invention are active against variousgram-positive and to a lesser extent gram-negative bacteria, andaccordingly find utility in human and veterinary medicine. The compoundsare particularly useful as anti-MRSA/MRCNS compounds.

The invention is further described in connection with the followingnon-limiting examples.

PREPARATIVE EXAMPLE 1 2-Thio-4-((Trimethyl)Silyloxymethyl)Thiazolo[5,4-b]Pyridine ##STR241##

Step 1

2-Chloro-3-nitro-4-picoline-N-oxide

2-Chloro-3-nitro-4-picoline (7g, 0.04 mol) was added to an ice cooledmixture of trifluoroacetic acid (25 mL) and 30% peracetic acid in aceticacid (15 mL). The mixture was allowed to warm to room temperature over30 minutes and was heated in a 60° C. oil bath for 5 hrs. The mixturewas partitioned between methylene chloride (100 mL) and water (100 mL).The pH was adjusted to 8 with 2.5N sodium hydroxide and the aqueouslayer was extracted with more methylene chloride 2×100 mL). The combinedmethylene chloride layers were dried with magnesium sulfate, filteredand evaporated to give 7.5 g of a 4:1 mixture of2-Chloro-3-nitro-4-picoline-N-oxide (79%) and2-Chloro-3-nitro-4-picoline, as determined by the integration of the NMRresonances. The two compounds could be separated by silicachromatography, but was used as is in the next reaction.

¹ H NMR (CDCl₃, 300 MHz) δ2.34(s, Me), 7.16 (d, H5), 8.31 (d, H6).

Step 2

2-Chloro-3-nitro-4-acetoxymethylpyridine

A 4:1 mixture of 2-Chloro-3-nitro-4-picoline-N-oxide and2-Chloro-3-nitro-4-picoline (7.2 g, 0.031 mol, based on the N-Oxide) wasdissolved in acetic anhydride (20 mL) and the solution was heated in a80° C. oil bath for 70 minutes. The solvents were removed under vacuumand the dark residue was partitioned between methylene chloride (100 mL)and saturated aqueous potassium carbonate (200 mL). The aqueous layerwas re-extracted with more methylene chloride (1×50 mL) and the combinedmethylene chloride layers were dried with magnesium sulfate, filteredand evaporated under vacuum. The crude solid was dissolved in methylenechloride (20 mL) and was loaded onto a silica gel column (E. Merck 60,230-400 mesh, 4×36 cm). The column was eluted with methylene chloridecollecting 25 mL fractions. Fractions 22-48 were combined and evaporatedto give substantially pure 2-chloro-3-nitro-4-acetoxymethylpyridine(1.75 g) as a white solid.

¹ H NMR (CDCl₃, 300 MHz) δ2.11 (s, Ac), 5.14 (s, CH₂ OAc), 7.41 (d, H5),8.51 (d, H6).

Step 3

2-thio-4-hydroxymethylthiazolo[5,4-b]pyridine

A suspension of sulfur (0.5 g, 15.6 mmol) and sodium sulfide nonahydrate(1.84 g, 7.66 mmol) in water (2 mL) was heated in a 50° C. oil bath for15 minutes. The amber colored solution was cooled to room temperature,2-chloro-3-nitro-4-acetoxymethylpyridine (0.5 g, 2.17 mmol) and carbondisulfide (0.5 mL, 8.3 mmol) were added and the mixture was heated in a70° C. oil bath for 3.5 hours under a nitrogen atmosphere. After coolingto room temperature, the suspension was filtered and the recoveredsulfur was washed with water (5 mL). The filtrate was acidified withacetic acid and 5% methanol/methylene chloride (20 mL) was added to thegummy precipitate. The aqueous layer was re-extracted with 5%methanol/methylene chloride (3×10 mL) and the combined extracts weredried with magnesium sulfate, filtered and evaporated to a solid (0.58g). The crude material was first purified on a silica column (E. Merck60, 230-400 mesh, 4×24 cm) using 5% methanol/methylene chloride as thedeveloping solvent and collecting 8 mL fractions. Fractions 5-10 werecombined and evaporated to a dark solid (220 mg). The solid was placedon preparative silica plates (Analtech, 4×500 micron, 5%methanol/methylene chloride as developing solvent), the product wasremoved, eluted with 20% methanol/methylene chloride and evaporated toprovide the title compound as a light orange solid (0.15 g).

¹ H NMR (DMSO-d6, 300 MHz) δ4.71 (d, CH₂ OH), 5.59 (t, CH₂ OH), 7.45 (d,H5), 8.38 (d, H6).

MS (M+1) 199

Step4

2-thio-4-((trimethyl)silyloxymethyl)thiazolo[5,4-b]pyridine

A solution of 2-thio-4-hydroxymethylthiazolo[5,4-b]pyridine (45 mg,0.227 mmol) was dissolved in bis(trimethylsilyl) acetamide (0.5 mL) andwas stirred at room temperature for 20 minutes under nitrogen. Thesolution was evaporated under vacuum and the residue was applied to aflash silica gel column (E. Merck 60, 230-400 mesh, 2.5×10 cm). Thecolumn was eluted with 1:1 hexane/diethylether and 3 mL fractions werecollected. Fractions 5-13 were combined and evaporated to give the titlecompound as a white solid (55mg).

¹ H NMR (CDCl₃, 300 MHz) δ0.25 (s, Si(TMS)₃), 4.94 (s, CH₂ O), 6.98 (d,H5), 8.31 (d, H6).

PREPARATIVE EXAMPLE 2 2-Thio-6-((Trimethyl)Silyloxymethyl)Thiazolo[5,4-b]Pyridine ##STR242##

Step 1

2-Chloro-3-nitro-6-picoline-N-oxide

2-Chloro-3-nitro-6-picoline (2 g, 11.6 mmol) was added to an ice cooledmixture of trifluoroacetic acid (6 mL) and 30% peracetic acid in aceticacid (6 mL). The mixture was allowed to warm to room temperature over 30minutes and was heated in a 60° C. oil bath for 5 hours. The mixture waspartitioned between methylene chloride (100 mL) and water (50 mL). ThepH was adjusted to 8 with 2.5N sodium hydroxide and the aqueous layerwas extracted with more methylene chloride (2×50 mL). The combinedmethylene chloride layers were dried with magnesium sulfate, filteredand evaporated to give the title compound as a white solid (1.6 g).

¹ H NMR (CDCl₃, 300 MHz) δ2.62(s, Me), 7.35 (d, ArH), 7.66 (d, ArH).

Step 2

2-Chloro-3-nitro-6-acetoxymethylpyridine

2-Chloro-3-nitro-6-picoline-N-oxide (1.6 g, 8.5 mmol) was dissolved inacetic anhydride (5 mL) and the solution was heated in a 60° C. oil bathfor 3 hours. The solvents were removed under vacuum and the dark residuewas partitioned between methylene chloride (30 mL) and saturated aqueouspotassium carbonate (100 mL). The aqueous layer was re-extracted withmore methylene chloride (2×40 mL) and the combined methylene chloridelayers were dried with magnesium sulfate, filtered and evaporated undervacuum. The crude solid was dissolved in methylene chloride (5 mL) andwas loaded onto a silica gel column (E. Merck 60, 230-400 mesh, 2.5×24cm). The column was eluted with methylene chloride collecting 8 mLfractions. Fractions 11-26 were combined and evaporated to give thetitle compound (0.42 g) as a white solid.

¹ H NMR (CDCl₃, 300 MHz) δ2.19 (s, Ac), 5.24 (s, CH₂ OAc), 7.45 (d, H5),8.23 (d, H4).

Step 3

2-thio-6-hydroxymethylthiazo[5,4-b]pyridine

A suspension of sulfur (0.5 g, 15.6 mmol) and sodium sulfide nonahydrate(2.0 g, 8.3 mmol) in water (3 mL) was heated in a 50° C. oil bath for 15minutes. The amber colored solution was cooled to room temperature,2-chloro-3-nitro-6-acetoxymethylpyridine (0.4 g, 1.73 mmol) and carbondisulfide (1 mL, 16.7 mmol) were added and the mixture was heated in a60° C. oil bath for 18 hours under a nitrogen atmosphere. After coolingto room temperature, the suspension was filtered and the recoveredsulfur was washed with water (5 mL). The filtrate was acidified with 2Nhydrochloric acid to pH 3 and 5% methanol/methylene chloride (20 mL) wasadded to the gummy precipitate. The aqueous layer was re-extracted with5% methanol/methylene chloride (3×10 mL) and the combined extracts weredried with magnesium sulfate, filtered and evaporated to a brown solid(0.58 g). The crude solid was purified on a silica column (E.Merck 60,230-400 mesh, 2.5×30 cm) using 5% methanol/methylene chloride as thedeveloping solvent and collecting 8 mL fractions. Fractions 26-46 werecombined and evaporated to give the title compound as a orange solid(240 mg).

¹ H NMR (DMSO-d6, 300 MHz) δ4.61 (s, CH₂ OH), 7.41 (d, ArH), 8.11 (d,ArH).

MS (M+1) 199

Step 4

2-thio-6-((trimethyl)silyoxymethyl)thiazolo[5,4-b]pyridine

A solution of 2-thio-6-hydroxymethylthiazolo[5,4-b]pyridine (230 mg,1.16 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) andbis(trimethylsilyl) acetamide (1.0 mL) and was stirred at roomtemperature for 20 minutes under nitrogen. The solution was evaporatedunder vacuum and the residue was applied to a flash silica gel column(E. Merck 60, 230-400 mesh, 2.5×5 cm). The column was eluted withmethylene chloride (60 mL), the eluent was evaporated and freeze-driedfrom benzene to give the title compound as a white solid (200 mg).

¹ H NMR (DMSO-d₆, 300 MHz) δ0.05 (s, Si(TMS)₃), 4.56 (s, CH₂ O), 7.48(d, ArH), 7.63 (d, ArH).

PREPARATIVE EXAMPLE 3 2-Thio-5-((Trimethyl)Silyloxymethyl)Thiazolo[5,4-b]Pyridine ##STR243##

Step 1

2-thio-5-(ethoxycarbonyl)thiazolo[5,4-b]pyridine

A suspension of sodium sulfide nonahydrate (1.5 g, 6.25 mmol) and sulfur(0.5 g, 15.6 mmol) in ethanol (20 mL) were heated in a 50° C. oil bathfor 10 minutes to give an amber colored solution. After cooling to roomtemperature, ethyl 2-chloro-3-nitronicotinate (0.58 g, 2.5 mmol) andcarbon disulfide (2 mL) were added and the mixture was heated in a 80°C. oil bath for 20 hours. The solvents were evaporated under vacuum andthe residue was partitioned between methylene chloride (30 mL) and water(5 mL). The pH was adjusted to 4 with acetic acid and the aqueous layerwas re-extracted with 5% methanol/methylene chloride (2×20 mL). Thecombined extracts were dried with magnesium sulfate, filtered andevaporated. Concentrated ammonium hydroxide was added and theprecipitated sulfur was filtered and the filtrate was evaporated. Theresidue was placed on a silica gel column (E. Merck 60, 230-400 mesh,2.5×30cm), the column was eluted with 5% methanol/methylene chloride and8 mL fractions were collected. Fractions 20-28 were combined andevaporated to give an impure light yellow solid (0.5 g). The collectedsolid was dissolved in hot ethanol (3 mL) and after cooling to roomtemperature the precipitate was filtered, washed with ethanol (5 mL) andprovided the title compound as a white crystalline solid (0.265 g).

¹ H NMR (CDCl₃, 300 MHz) δ1.43 (t, CH₂ CH₃), 4.45 (q, CH₂ CH₃), 8.02 (d,H4), 9.02 (d, H6).

Step 2

2-thio-5-(hydroxymethyl)thiazolo[5.4-b]pyridine

2-thio-5-(ethoxycarbonyl)thiazolo[5,4-b]pyridine (120 mg, 0.5 mmol) wasdissolved in tetrahydofuran (3 mL) and was treated with lithium aluminumhydride (1 mL, 1 mmol, 1M solution in tetrahydrofuran) at roomtemperature under nitrogen. After 30 minutes, water (0.5 mL) was addedcautiously and the granular precipitate was filtered through solka-floc.The filtrate was evaporated under vacuum and provided the title compoundas a solid (120 mg).

¹ H NMR (DMSO-d₆, 300 MHz) δ4.58 (s, CH₂ OH), 7.55 (d, H4), 8.32 (d,H6).

MS (M+1) 199

Step 3

2-thio-5-((trimethyl)silyloxymethyl)thiazolo[5,4-b]pyridine

A solution of 2-thio-5-hydroxymethylthiazolo[5,4-b]pyridine (120 mg,0.61 mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) andbis(trimethylsilyl) acetamide (0.5 mL) and was stirred at roomtemperature for 20 minutes under nitrogen. The solution was evaporatedunder vacuum and the residue was applied to a flash silica gel column(E. Merck 60, 230-400 mesh, 2.5×5 cm). The column was eluted withmethylene chloride (50 mL) and evaporated to give a white solid. Thesolid was triturated with hexanes, was filtered and provided the titlecompound as a white solid (64 mg).

¹ H NMR (CDCl₃, 300 MHz) δ0.19 (s, Si(TMS)₃), 4.77 (s, CH₂ O), 7.53 (s,H4), 8.36 (s, H6).

PREPARATIVE EXAMPLE 4 6-Hydroxymethyl-2-Mercaptobenzothiazole ##STR244##

Step 1

2-Amino-6-ethoxycarbonylbenzothiazole

A solution of ethyl 4-aminobenzoate (8.26 g, 0.05 mol) in acetic acid(100 mL) was treated with potassium thiocyanate (14.58 g, 0.15 mol) andstirred 10 minutes at room temperature to dissolve the salt. Theresulting solution was cooled in an ice bath and stirred while bromine(2.6 mL, 0.05 mol) was added dropwise over 15 minutes. The cooling bathwas removed and the mixture was stirred at room temperature for 2.25hours. The mixture was stored at 5° C. for 5 hours, then filtered toremove the yellow precipitate. The filter cake was washed with diethylether (2×50 mL) and water (2×100 mL) and dried under vacuum to give2-amino-6-ethoxycarbonylbenzothiazole (2.54 g) as a yellow solid.

The acetic acid filtrate and ether washings were combined and evaporatedunder vacuum to an amber gum. The water washings from the yellow solidwere added and the mixture was neutralized with solid sodiumbicarbonate. The resulting precipitate was collected, washed with waterand dried under vacuum to a pale tan solid (8.74 g). Proton NMR analysisof this material revealed a 65:35 mixture of ethyl4-amino-3-thiocyanatobenzoate to 2-amino-6-ethoxycarbonylbenzothiazole.The mixture was dissolved in acetic acid (100 mL) and stirred at roomtemperature for 42 hours. A fine precipitate formed. The mixture wasfiltered and the cake washed with diethyl ether and dried under vacuumto give additional 2-amino-6-ethoxycarbonylbenzothiazole (2.28 g) as acream colored powder.

¹ H NMR (DMSO-d₆, 500 MHz) δ1.30 (t, CH₃), 4.28 (q, CH₂), 7.38 (d, H-4),7.82 (dd, H-5), 8.07 (br s, NH₂), and 8.29 (d, H-7).

¹³ C NMR (DMSO-d₆, 125.7 MHz) δ14.2, 60.4, 116.8, 122.3, 122.7, 127.2,130.5, 155.5, 165.5, and 169.8.

Step 2

2-Bromo-6-ethoxycarbonylbenzothiazole

A mixture of copper(II) bromide (2.70 g, 12.09 mmol) and anhydrousacetonitrile (50 mL) was purged with nitrogen, cooled in an ice bath,treated with tert-butyl nitrite (1.8 mL, 15.13 mmol), stirred 10 minutesat 0°-5° C, and then treated with solid 2-amino-6ethoxycarbonylbenzothiazole (2.24 g, 10.08 mmol). The cooling bath wasremoved and the mixture was stirred at room temperature for 2 hours. Themixture was diluted with water (300 mL) and extracted with diethyl ether(2×100 mL). The extracts were filtered to remove copper salts, thenwashed with water (100 mL) and brine (100 mL), dried over sodiumsulfate, filtered and evaporated under vacuum to provide crude2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g) as an orange-tan solid.

¹ H NMR (CDCl₃, 500 MHz) δ1.42 (t, CH₃), 4.42 (q, CH₂), 8.02(d, H-4),8.15 (dd, H-5), and 8.53 (d, H-7).

¹³ C NMR (CDCl₃, 125.7 MHz) δ14.3, 61.5,122.5, 122.9, 127.8, 137.2,142.3, 155.0, and 165.7.

Step 3

6-Ethoxycarbonyl-2-mercaptobenzothiazole

The crude 2-bromo-6-ethoxycarbonylbenzothiazole (1.90 g, 6.64 mmol) fromStep 2 was suspended in absolute ethanol (35 mL) and treated withpotassium hydrogen sulfide (0.96 g, 13.3 mmol). The mixture was placedunder a nitrogen atmosphere, stirred, and heated in an oil bath at 80°C. The benzothiazole starting material gradually went into solution.After heating for 30 minutes, the mixture was cooled in an ice bath,treated with 1N hydrochloric acid (13.5 mL), and evaporated undervacuum. The residue was partitioned between ethyl acetate (100 mL) andwater (100 mL) and the aqueous phase extracted with more ethyl acetate(50 mL). The combined ethyl acetate solution was washed with brine (50mL), dried over sodium sulfate, filtered and evaporated under vacuum toa yellow-tan solid (1.56 g). This material was triturated with diethylether and dried under vacuum to provide6-ethoxycarbonyl-2-mercaptobenzothiazole (1.14 g) as a pale tan powder.

¹ H NMR (DMSO-d₆, 500 MHz) δ1.31 (t, CH₃), 3.33 (br s, SH), 4.30(q,CH₂), 7.35 (d, H-4 ), 7.94 (d, H-5), and 8.29 (s, H-7).

¹³ C NMR (DMSO-d₆, 125.7 MHz) δ14.1, 60.9, 112.1, 123.2, 125.5, 128.4,129.7, 144.6, 165.0, and 191.8.

Step 4

6-Hydroxymethyl-2-mercaptobenzothiazole

A solution of 6-ethoxycarbonyl-2-mercaptobenzothiazole (1.14 g, 4.64mmol) in anhydrous tetrahydrofuran (14 mL) was heated to reflux under anitrogen atmosphere and stirred while 1M lithium aluminum hydride intetrahydrofuran (4.7 mL) was added dropwise. The resulting mixture wasstirred and heated at reflux for one hour, then cooled in an ice bathand cautiously treated with 2N hydrochloric acid. The mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (3×25 mL).The combined extracts were washed with brine (25 mL), dried over sodiumsulfate, filtered and evaporated under vacuum to provide6-hydroxymethyl-2-mercaptobenzothiazole (0.89 g) as a pale yellow solid.

¹ H NMR (DMSO-d₆, 500 MHz) δ3.33 (br s, SH), 4.51 (s, CH₂ OH), 5.28 (brs, CH₂ OH), 7.25 (d, H-4), 7.32 (dd, H-5), and 7.60 (d, H-7).

¹³ C NMR (DMSO-d₆, 125.7 MHz) δ62.5, 112.0, 119.4, 125.7, 129.3, 139.0,140.1, and 189.6.

PREPARATIVE EXAMPLE 5 7-HYDROXYMETHYL-2-MERCAPTOBENZOTHIAZOLE ##STR245##

Step 1

7-Carboxy-2-mercaptobenzothiazole

2-Chloro-3-nitrobenzoic acid (8.06 g, 0.04 mol) in 1N sodium hydroxide(50 mL) was added to a polysulfide solution made from sodium sulfidenonahydrate (28.82 g, 0.12 mol) and sulfur (9.60 g, 0.30 mol) in water(30 mL). The resulting mixture was stirred and heated at reflux for 5.5hours. The reaction mixture was cooled to 45° C., treated with carbondisulfide (4.81 mL, 0.08 mL), and stirred at 45° C. for 20 hours. Themixture was cooled in an ice bath and neutralized by slowly addingacetic acid (7 g). The solid precipitate was collected, washed withice-cold water, suspended in saturated sodium carbonate solution (100mL), and filtered to remove insolubles. The filtrate was acidified withacetic acid (33 g) and filtered to collect the insoluble material. Thefilter cake was dried under vacuum to afford crude7-carboxy-2-mercaptobenzothiazole (0.70 g) as a brownish gray solid.

IR (KBr) 3448 (br), 1570, 1507, 1458, 1419, 1393, 1333, 1259, 1076,1040, 984, 768, 668, 657, and 629 cm⁻¹.

¹ H NMR (DMSO-d₆, 500 MHz) δ7.18 (t), 7.30 (d), and 7.62 (d).

¹³ C NMR (DMSO-d₆, 125.7 MHz) δ115.4, 122.8, 124.7, 131.3, 134.2, 149.0,169.2, and 191.1.

Step 2

7-Hydroxymethyl-2-mercaptobenzothiazole

A mixture of crude 7-carboxy-2-mercaptobenzoic acid (480 mg, 2.27 mmol)and anhydrous tetrahydrofuran (7 mL) was placed under a nitrogenatmosphere and sonicated for a few minutes to give a fine suspension.The mixture was stirred and heated at reflux while 1.0M lithium aluminumhydride in tetrahydrofuran (4.5 mL) was cautiously 5 added. Theresulting mixture was heated at reflux for 60 minutes, then sonicated atroom temperature for 15 minutes. The mixture was cooled in an ice bath,stirred, and acidified with 2N hydrochloric acid (18 mL). The mixturewas diluted with water (18 mL) and extracted with ethyl acetate (4×20mL). The combined extracts were washed with brine (20 mL), dried oversodium sulfate, swirled with charcoal, filtered, and evaporated undervacuum to afford 7-hydroxymethyl-2-mercaptobenzothiazole (228 mg) as apale yellow powder.

¹ H NMR (DMSO-d₆, 500 MHz) δ3.32 (s, SH), 4.62 (d, CH₂ OH), 5.66 (t, CH₂OH), 7.13 (d, H-6), 7.19 (d, H-4), and 7.33 (t, H-5).

¹³ C NMR (DMSO-d₆, 125.7 MHz) δ61.7, 110.8, 121.2, 126.6, 127.0, 135.9,141.9, and 190.7.

PREPARATIVE EXAMPLE 6 4-HYDROXYMETHYL-2-MERCAPTOBENZOTHIAZOLE ##STR246##

Step 1

4-Carboxy-2-mercaptobenzothiazole

Substitution of 3-chloro-2-nitro-benzoic acid for2-chloro-3-nitro-benzoic acid in the procedure of Preparative Example 7afforded 4-carboxy-2-mercaptobenzothiazole as a solid.

Step 2

4-carboxybenzothiazol-2-thiol

A solution of 4-carboxy-2-mercaptobenzothiazole (1.06 g, 5 mmol) inanhydrous tetrahydrofuran (15mL) was cooled in an ice bath undernitrogen. A solution of lithium aluminum hydride (10 mL, 10 mmol) wasadded dropwise over 3 minutes and the flask was removed from the icebath and allowed to warm to room temperature. After 10 minutes, themixture was heated in a 60° C. oil bath for one hour. After cooling inan ice bath, hydrochloric acid (40 mL, 2N) was carefully added and theresulting solution was partitioned between ethyl acetate (60 mL) andwater (40 mL). The ethyl acetate was removed and the aqueous layer wasre-extracted with more ethyl acetate (2×60 mL). The combined extractswere washed with brine (20 mL), dried with magnesium sulfate, filteredand evaporated under vacuum to give a light yellow foam. The solid wassuspended in a mixture of water (5 mL) and methylene chloride (10 mL).The pH was adjusted to 10 with 1N sodium hydroxide, the aqueous layerwas filtered through a 0.45 micron acrodisc and the pH of the filtratewas adjusted to 3 with 2N hydrochloric acid. The precipitate wasfiltered, washed with water (20 mL) and the collected solid was driedovernight under a stream of nitrogen to give the title compound as alight yellow solid (0.63 g).

¹ H NMR (DMSO-d₆, 500 MHz) δ4.69 (s, CH₂ OH), 5.29 (s, CH₂ OH), 7.26 (t,ArH-6'), 7.38 and 7.55 (two d, ArH-5' and ArH-7') and 13.4 (s, NH).

¹³ C NMR (DMSO-d₆, 500 MHz) δ59.67, 120.44, 124.48, 125.91, 127.72,129.55, 138.79 and 190.66.

PREPARATIVE EXAMPLE 2

4'-METHOXYBENZYL 7β-PHENYLACETAMIDO-3-TRIFLUORMETHANESULFONYLOXY-CEPH-3-EM-4-CARBOXYLATE ##STR247##

4'-methoxybenzyl 7β-phenylacetamido-3-hydroxy-ceph-3-em-4-carboxylate(9.09 g) was dissolved in CH₂ Cl₂ (250 mL) and cooled to -78° C. undernitrogen. Et₃ N (3.12 mL, 1.1 eq) was added followed 5 minutes later bytrifluoromethanesulfonic anhydride (3.71 mL, 1.1 eq). The reactionmixture was stirred at -78° C. for 20 min. and then allowed to come toroom temperature rapidly. The reaction mixture was diluted with CH₂ Cl₂to give a clear solution and then washed with water, pH 7 buffer (0.5M),saturated. sodium chloride, dried over sodium sulfate. Evaporation ofthe solvent to about 100 mL under vacuum without heat gave whitecrystals which were filtered off, washed with ether and dried to give6.4 g of product. Dilution of the mother liquor with ether followed bycooling gave another 0.7 g of the desired product.

NMR (CDCl₃, 200 MHz) δ3.53 (ABq, J-16, S--CH₂); 3.62 (ABq, J=15, C₆ H₅CH₂ ); 3.78 (s, OCH₃); 4.9 (d, J=5.5, C-6 H); 5.24 (ABq, J=12, CH₂ C₆ H₄OCH₃); 5.86 (d of d, J=5.5, J=8, C-7 H); 6.13 (d, J=8, NH); 7.2-7.45 (m,Ar H).

PREPARATIVE EXAMPLE 8

4'-METHOXYBENZYL7β-PHENYLACETAMIDO-3-(5-HYDROXYMETHYL-(BENZTHIAZOL-2-YL)THIO-CEPH-3-EM-4-CARBOXYLATE##STR248##

4'-Methoxybenzyl7β-phenylacetamido-3-trifluoromethanesulfonyloxy-ceph-3-em-4-carboxylate(2.34 g, 4 mmole) was suspended in methylene chloride (40 mL) and cooledto -10° C. In another flask, sodium hydride (60% suspension in mineraloil, 160 mg. 4 mmole) was suspended in THF (4 mL). To this was added5-hydroxymethyl-2-mercaptobenzthiazole (780 mg, 4 mmole) and the mixturestirred for 30 min. at room temperature. The resulting solution wasadded dropwise over 20 min. to the suspension of the triflate with rapidstirring. The reaction was allowed to come to room temperature andtreated with KH₂ PO₄ (0.5M solution, 10 mL) and water (50 mL). A whiteprecipitate formed which was filtered off, washed with water and thenwashed with ether and dried under vacuum to give the desired Δ³ product(0.97 g). The two phase filtrate was separated and the organic phase waswashed with water and saturated NaCl solution, dried over Na₂ SO₄ andevaporated to give the crude product. Crystallization from hotchloroform gave more of the desired product (0.48 g). Total yield 1.45g.

NMR:(CDCl₃, 200 MHz) δ3.5 (d, J=16, S--CH₂); 3.66 (d, J=15, C₆ H₅ CH₂ );3.78 (s, OCH₃); 3.9 (d, J=16, S--CH₂); 4.84(s, ArCH₂ OH); 5.05 (d,J=5.5, C-6 H); 5.23 (s, CH₂ C₆ H₄ OCH₃); 5.89 (d of d, J=5.5, J=8, C-7H); 6.08 (d, J=8, NH); 6.7-8 (m, Ar H).

EXAMPLE 1

4'-METHOXYBENZYL7β-AMMONIUM-3-(5-CHLOROMETHYL-2-BENZTHIAZOLYLTHIO)-CEPH-3-EM-4-CARBOXYLATEp-TOLUENESULFONATE ##STR249##

4'-Methoxybenzyl7β-phenylacetamido-3-(5-hydroxymethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate(1.26 g, 2 mmole) was suspended in CH₂ Cl₂ and cooled to -15° C. underN₂. Pyridine (3.2 mL) was added followed by PCl₅ (8% solution in CH₂Cl₂, 32 mL). The reaction mixture was stirred at -15° C. for 1.5 hrs,then cooled to -30° C. MeOH (10 mL) was added dropwise over 5 min. andstirring was continued for 1.5 hrs at -15° C. The ice bath was removedand the mixture was allowed to come to room temperature and stirredanother 1.5 hrs.

KH₂ PO₄ solution (40 mL, 0.5M ) was added and the mixture stirredanother 0.5 hr. The solvent was removed under reduced pressure. Theresidue was taken up in CH₂ Cl₂. The aqueous layer was separated andextracted with CH₂ Cl₂. The combined organic phase was washed withsaturated NaCl solution, dried over Na₂ SO₄ and evaporated to dryness.The residue was taken up in CH₂ Cl₂ (10 mL) and treated with a solutionof p-toluenesulfonic acid (0.57 g) in EtOAc (10 mL) to give a gum whichon trituration gave a solid. The solid was filtered, washed with etherand dried. The filtrate and washings gave a second crop of solid whichwas filtered, washed with ether and dried. The combined solid was 1.1 gof the title product.

EXAMPLE 2

4'-METHOXYBENZYL7β-AMINO-3-TRIFLUORMETHANESULFONYLOXY-CEPH-3-EM-4-CARBOXYLATE p-TOLUENESULFONIC ACID SALT ##STR250##

4'-methoxybenzyl7β-phenylacetamido-3-trifluormethanesulfonyloxy-ceph-3-em-4-carboxylate(1.17 g) was dissolved in CH₂ Cl₂ 40 mL and cooled to -15° C. undernitrogen. Pyridine (1.6 mL) was added followed by a 8% solution of PCl₅in methylene chloride (16 mL). The reaction mixture was allowed to stirat -15° to -10° C. for 1 hr. The reaction mixture was cooled to -30° C.and treated with MeOH (10 mL). The temperature was raised to -15° C. andthe mixture was stirred at -15° to 10° C. for 1 hour. The ice bath wasremoved and the mixture stirred for another hour. KH₂ PO₄ (0.5M, 40 mL)was added and the reaction mixture was stirred at room temperature for0.5 hr. (Reaction was at pH 2).

The organic solvents were removed by evaporation under reduced pressureand the residue was partitioned between CH₂ Cl₂ and water. The aqueousphase was extracted once with 40 mL methylene chloride and the combinedorganic extract was washed once with pH 7 buffer, then with saturated.NaCl, dried over Na₂ SO₄ and evaporated to dryness. The residue (1.52 g)was dissolved in EtOAc (10 mL) and treated with a solution ofp-toluenesulfonic acid (450 mg in 8.0 mL EtOAc). This was diluted toturbidity with hexane. Scratching the flask induced crystallization. Thecrystals were allowed to stand overnight at 5° C. and were filtered offand washed with ether and dried to give the product (1.09 g).

EXAMPLE 3

4'-METHOXYBENZYL7β-[2-(TRIPHENYLMETHYLAMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-TRIFLUORMETHANESULFONYLOXY-CEPH-3-EM-4-CARBOXYLATE##STR251##

2-(Triphenylmethylamino)-Z-(methoxyimino)-4-thiazoleacetic acidhydrochloride (105 mg, 1.1 eq) was dissolved in sieve-dried CH₂ Cl₂ (3mL) and cooled to -10° C. under nitrogen. Pyridine (37.4 μL, 2.4 eq.)was added followed by POCl₃ (22.2 μL, 1.2 eq). The reaction mixture wasstirred at -10° C. for 45 min. To this was added 4'-methoxybenzyl7β-amino-3-trifluoromethanesulfonyloxy-ceph-3-em-4-carboxylate p-toluenesulfonic acid salt (128 mg, 1.0 eq) and pyridine (18 μL) dissolved in1.5 mL CH₂ Cl₂. The reaction mixture was stirred at -10° C. for 0.5 hrand the ice bath was removed. When the reaction mixture came to roomtemperature (about 5 min.) the reaction mixture was diluted withmethylene chloride and washed with pH 7 buffer, then with 0.01N HCl,then with pH 7 buffer, dried over Na₂ SO₄ and evaporated. The residuewas the crude product which was purified by preparative reverse phasechromatography on a C-18 column, using 80% CH₃ CN/water as eluantfollowed by 90% CH₃ CN/water. The product came off in the 90% CH₃CN/water eluate. The fraction containing the product was evaporated toremove the CH₃ CN and the residue was extracted with methylene chloride,dried over Na₂ SO₄ and evaporated to give the pure product (95 mg).

NMR:(CDCl₃, 300 MHz) δ3.41 (d, J=17, S--CH₂); 3.77 (s, OCH₃); 3.72 (d,J=17, S--CH₂); 4.02(s, OCH₃); 5.07 (d, J=5.0, C-6 H); 5.21 (ABq, CH₂ C₆H₄ OCH₃); 5.9 (d of d, J=5.0, J=8, C-7 H); 6.6-7.4 (m, Ar H and NH).

EXAMPLE 4

7β-[2-AMINO(THIAZOL-4-YL)-2-Z-(2-FLUORO)-ETHOXYIMINO]ACETAMIDO-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR252##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-(2-fluoro)-ethoxyimino]acetamido-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate##STR253##

4'-Methoxybenzyl7β-ammonium-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylatep-toluenesulfonate (141 mg, 0.2 mmole) was taken up in CH₂ Cl₂ (10 mL)and washed with NaHCO₃ solution (10%, 5 mL), pH 7 buffer (0.4M,phosphate) followed by saturated NaCl solution, then dried over Na₂ SO₄and evaporated to give the free amine (117 mg).

NMR:(CDCl₃, 200 MHz) δ3.58 (d, J=18, S--CH₂); 3.74 (s, C₆ H₅ CH₂ , OCH₃); 3.95 (d, J=18, S--CH₂); 4.72(s, ArCH₂ Cl); 4.85 (d, J=5.5, C-6 H);5.07 (d, J=5.5, C-7 H); 5.24 (s, CH₂ C₆ H₄ OCH₃); 6.7-8 (m, Ar H).

2-(Triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino]acetic acid(91 mg) was dissolved in CH₂ Cl₂ (3.5 mL) and cooled to -15° C. underN₂. Pyridine (19.4 μl, 1.2 eq) was added followed by POCl₃ (22.8 μl, 1.2eq). The reaction mixture was stirred at -15° C. for 0.5 hr. To this wasadded a solution of the free amine from above in CH₂ Cl₂ (1 mL) followedby pyridine (18 μl) and stirring was continued for 0.5 hr. The ice bathwas removed and the reaction warmed to room temperature over 15 min. Thereaction mixture was diluted with CH₂ Cl₂ and washed with pH 7 bufferfollowed by 0.1N HCl, pH 7 buffer, saturated. NaCl solution., dried overMgSO₄ and evaporated. Preparative TLC gave the desired product (78 mg).

NMR:(CDCl₃, 200 MHz) δ3.53 (d, J=18, S--CH₂); 3.77 (s, OCH₃); 3.95 (d,J=18, S--CH₂); 4.4-4,85(m, O--CH₂ --CH₂ --F) 4.73(s, ArCH₂ C₁); 5.18 (d,J=5.5, C-6 H); 5.25 (s, CH₂ C₆ H₄ OCH₃); 6.0 (d of d, J=5.5, J=8, C-7H); 6.6-8 (m, Ar H and NH).

Step 2

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-(2-fluoro)-ethoxyimino]acetamido-3-(5-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate##STR254##

4'-Methoxybenzyl 7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino]acetamido-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate(78 mg) was treated with KI (98 mg, 0.59 mmol) and allowed to stir forapproximately 8 hrs at room temperature. The solvent was removed underreduced pressure and the residue taken up in chloroform. Uponevaporation, the desired iodide was obtained. (82 mg).

NMR:(CDCl₃, 200 MHz) δ3.54 (d, J=18, S--CH₂); 3.78 (s, OCH₃); 3.96 (d,J=18, S--CH₂); 4.4-4.85(m, O--CH₂ --CH₂ --F) 4.59 (s, ArCH₂ I); 5.18 (d,J=5.5, C-6 H); 5.25 (s, CH₂ C₆ H₄ OCH₃); 6.0 (d of d, J=5.5, J=8, C-7H); 6.6-8 (m, Ar H and NH).

IR: λmax, cm⁻¹ ; 1788, 1734, 1682.

Step 3

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-(2-fluoro)-ethoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethanesulfonate) ##STR255##

4'-Methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino]acetamido-3-(5-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate(82 mg) was dissolved in CH₃ CN (2 mL) under N₂ and treated with1-carbamoylmethyl-4-aza-1-azoniabicyclo[2.2.2]octane trifluoromethylsulfonate (25.5 mg), followed by AgOTf (20.5 mg) dissolved in CH₃ CN(0.5 mL). The reaction mixture was stirred under N₂ for 1 hr. The solidswere filtered off through a bed of celite, and washed with CH₃ CN (10mL). The combined filtrate and washings were evaporated to give thedesired product (110 mg). NMR:(CD₃ CN, 200 MHz) δ3.36 and 3.78(2m,N⁺--CH₂ --CH₂ --N⁺); 3.75 (s, OCH₃); 4.16 (d, SCH₂, J=17); 4.25 (s,Ar--CH₂ --N⁺); 5.46 (d, J-5.5, C-6 H); 6.05 (d of d, J=5.5, J=7, C-7 H);6.8 to 8.8 (m, ArH and NH)

Step 4

7β-[2-amino(thiazol-4-yl)-2-Z-(2-fluoro)-ethoxyimino]acetamido-3-{5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatechloride ##STR256##

4'-Methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate) (110 mg) was dissolved in anisole (1 mL),under N₂ and treated with trifluoroacetic acid (3 mL).

The reaction was stirred at room temperature for 15 minutes. Toluene wasadded and the mixture was evaporated to dryness and the procedure wasrepeated twice. The residue was partitioned between hexane and CH₃ CN/H₂O and the hexane was extracted once more with 10% CH₃ CN/H₂ O. Theaqueous phase was filtered through a 0.45 μm filter and purified bypreparative HPLC on a Waters Delta-Pak C-18, 100 Å, 19 mm×30 cm column,using a 0-25% CH₃ CN/0.12M NH₄ Cl, 20 min. gradient. The solution fromthe column containing the product was concentrated and loaded on a 5 mLbed of Amberchrome 161C resin packed in water, washed with water (25 mL)followed by 50% CH₃ CN/H₂ O (20 mL). The product eluting in the 50% CH₃CN/H₂ O eluant was freeze dried to give the product (17.1 mg).

NMR:(D₂ O, 500 MHz) δ3.58 (d, J=17, S--CH₂); 3.97 (d, J=17, S--CH₂);4.04 and 4.21 (2m, N⁺ --CH₂ --CH₂ --N⁺); 4.35 (s, CO--CH₂ --N⁺); 4.40and 4.46 (2 d of d, O--CH₂ --CH₂ --F); 4.68 and 4.77 (2t, O--CH₂ --CH₂--F); 4.85 (s, Ar--CH₂ --N⁺); 5.38 (d, J=5.5, C-6 H); 5.83 (d, J=5.5,C-7 H); 6.97 (s, Thiazolyl H); 7.4 (d, Benzthiazolyl 6H); 7.80 (s,Benzthiazolyl 4H); 7.91 (d, Benzthiazolyl 7H).

EXAMPLE 5

7β-[2-(AMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR257##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

Substitute 2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]aceticacid hydrochloride for2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino]acetic acidin the procedure of example 4, step 1, except that an extra 1 equivalentof pyridine is used in the acid chloride forming reaction, to obtain thedesired product.

NMR:(CDCl₃, 200 MHz) δ3.54 (d, J=16, S--CH₂); 3.77 (s, OCH₃); 3.97 (d,J=16, S--CH₂); 4.07(s, OCH₃); 4.73(s, ArCH₂ Cl); 5.16 (d, J=5.5, C-6 H);5.25 (s, CH₂ C₆ H₄ OCH₃); 6.0 (d of d, J=5.5, J=8, C-7 H); 6.6-8 (m, ArH and NH).

Step 2

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-(5-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

4'-Methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate(74.2 mg, 0.077 mmole) dissolved in acetone (2.2 mL) was treated with KI(98 mg, 0.59 mmole) and the mixture allowed to stir overnight at roomtemperature. The solvent was removed under reduced pressure and theresidue was taken up in CHCl₃ and filtered. The filtrate was evaporatedto give the product (83 mg).

NMR:(CDCl₃, 200 MHz) δ3.54 (d, J=16, S--CH₂); 3.77 (s, ArOCH₃); 3.94 (d,J=16, S--CH₂); 4.07(s, OCH₃); 4.58 (s, ArCH₂ I); 5.17 (d, J=5.5, C-6 H);5.25 (s, CH₂ C₆ H₄ OCH₃); 6.0 (d of d, J=5.5, J=8, C-7 H); 6.7-8 (m, ArH and NH).

Step 3

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate)

Starting with the product of Step 2 (81 mg) and following the procedureof example 4, step 3 one obtains the desired product (112 mg).

Step 4

7β-[2-(aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]benzthiazol-2-yl-]thio-ceph-3-em-4-carboxylatechloride

4'-Methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate) (104.8 mg) was dissolved in anisole (1.3mL), under N₂ and treated with trifluoroacetic acid (3.5 mL). Thereaction was stirred at room temperature for 10 min. Toluene was addedand the mixture was evaporated to dryness and the procedure was repeatedtwice. The residue was treated with hexane and the hexane solublematerial decanted off. The procedure was repeated again and the residualhexane was removed by evacuation. The residue was treated with water andsufficient CH₃ CN to effect solubilization. The pH was adjusted to 5.9and filtered through a 0.45 μm filter and purified by reverse phase HPLCas described in example 6, step 4, to give the product (11.5 mg).

NMR:(D₂ O, 300 MHz) δ3.58 (d, J=16, S--CH₂); 4.0(s, OCH₃); 4.1 and 4.26(2m, N⁺ --CH₂ --CH₂ --N⁺); 4.4 (s, CO--CH₂ --N⁺); 4.8 (s, Ar--CH₂--N.sup.); 5.41 (d, J=5.5, C-6 H); 5.8 (d, J=5.5, C-7 H); 6.98 (s,Thiazolyl H); 7.46 (d, Benzthiazolyl 6H); 7.86 (s, Benzthiazolyl 4H);7.98 (d, Benzthiazolyl 7H).

EXAMPLE 6

7β-[2-(AMINOTHIAZOL-4-YL)-2-Z-(HYDROXYIMINO]ACETAMIDO-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR258##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-triphenylmethoxyimino]acetamido-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

Substituting2-(triphenylmethylaminothiazol-4-yl)-2-Z-triphenylmethoxyimino]aceticacid for2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino]acetic acidin the procedure of example 4, step 1, one obtains the desired product.

NMR: (CDCl₃, 200 MHz) δ3.35 (d, J=18, S--CH₂); 3.76 (s, OCH₃); 3.89 (d,J=18, S--CH₂); 4.71 (s, ArCH₂ Cl); 5.19 (d, J=5.5, C-6 H); 5.26 (s, CH₂C₆ H₄ OCH₃); 6.13 (d of d, J=5.5, J=8, C-7 H); 6.45-8 (m, Ar H and NH).

Step 2

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-triphenylmethoxyimino]acetamido-3-(5-iodomethyl-2-benzthiazolylthio)-Ceph-3-em-4-carboxylate

Following the procedure of example 5, step 2 and starting with theproduct of step 1, (131 mg) one obtains the desired product (141 mg).

NMR: (CDCl₃, 200 MHz) δ3.33 (d, J=18, S--CH₂); 3.76 (s, OCH₃); 3.88 (d,J=18, S--CH₂); 4.57 (s, ArCH₂₁); 5.17 (d, J=5.5, C-6 H); 5.27 (s, CH₂ C₆H₄ OCH₃); 6.11 (d of d, J=5.5, J=8, C-7 H); 6.45-8 (m, Ar H and NH).

Step 3

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-triphenylmethoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate)

Starting with the product of Step 2 and following the procedure ofExample 4, Step 3, one obtains the desired product.

Step4

7β-[2-(aminothiazol-4-yl)-2-Z-(hydroxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-Ceph-3-em-4-carboxylate chloride

4'-Methoxybenzyl7β-[2-(Triphenylmethylaminothiazol-4-yl)-2-Z-Triphenylmethoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate) from step 3 (78 mg) was treated accordingto the procedure of example 5, step 4, to give the desired product.

NMR: (D₂ O,500 MHz) δ3.54 (d, J=17, S--CH₂); 4.04 and 4.22 (2m, N⁺ --CH₂--CH₂ --N⁺); 4.36 (s, CO--CH₂ --N⁺); 4.88 (s, Ar--CH₂ --N⁺); 5.38 (d,J=5.0, C-6 H); 5.86 (d, J=5.0, C-7 H); 6.91 (s, Thiazolyl H); 7.42 (d,Benzthiazolyl 6H); 7.86 (s, Benzthiazolyl 4H); 7.95 (d, Benzthiazolyl7H).

EXAMPLE 7

7β-[2-(AMINOTHIAZOL-4-YL)-2-Z-BENZYLOXYIMINO]ACETAMIDO-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR259##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-benzyloxyimino]acetamido-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

Substituting2-(triphenylmethylaminothiazol-4-yl)-2-Z-benzyloxyimino]acetic acid for2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino]acetic acidin the procedure of example 4, step 1, one obtains the desired product.

NMR: (CDCl₃, 500 MHz) δ3.36 (d, J=18, S--CH₂); 3.77 (s, OCH₃); 3.83 (d,J=18, S--CH₂); 4.74(s, ArCH₂ Cl); 5.10 (d, J=5.1, C-6 H); 5.25 (s, CH₂C₆ H₄ OCH₃); 5.34 (s, CH₂ C₆ H₅); 5.96 (d of d, J=5.5, J=8, C-7 H);6.7-8 (m, Ar H and NH).

IR: λ^(max), cm⁻¹ ; 1784, 1732, 1682.

Step 2

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-benzyloxyimino]acetamido-3-(5-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

Following the procedure of Example 5, Step 2, but starting with theproduct of step 1, one obtains the desired product.

NMR: (CDCl₃, 500 MHz) δ3.36 (d, J=18, S--CH₂); 3.77 (s, OCH₃); 3.82 (d,J=18, S--CH₂); 4.61 (s, ArCH₂ I); 5.09 (d, J=5.1, C-6 H); 5.25 (s, CH₂C₆ H₄ OCH₃); 5.34 (s, CH₂ C₆ H₅); 5.95 (d of d, J=5.5, J=8, C-7 H);6.7-8 (m, Ar H and NH).

Step 3

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-benzyloxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2,2,2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate)

Starting with the product of Step 2 and following the procedure ofExample 5, Step 3, one obtains the desired product.

Step4

7β-[2-(aminothiazol-4-yl)-2-Z-benzyloxyiminolacetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatechloride

4'-Methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-benzyloxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate) from step 3 (83.4 mg) was treatedaccording to the procedure of example 5, step 4, to give the desiredproduct (15.1 mg).

NMR: (30% CD₃ COCD₃ /D₂ O, 500 MHz) δ3.37 (d, J=1 7, S--CH₂); 4.15 and4.32 (2m, N⁺ --CH₂ --CH₂ --N⁺); 4.44 (s, CO--CH₂ --N⁺); 4.98 (s, Ar--CH₂--N⁺ ); 5.25 (s, CH₂ C₆ H₅); 5.34 (d, J=5.0, C-6 H); 5.84 (d, J=5.0, C-7H); 6.97 (s, Thiazolyl H); 7.2-8.2(m, ArH).

EXAMPLE 8

7β-[2-(AMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-{[5-(3-METHYLIMIDAZOLIUM)-METHYL]BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATE##STR260##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(3-methylimidazolium)-methyl]benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylateiodide

4'-Methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-(5-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate(127.6 mg, 0.12 mmole) in CH₃ CN(4.5 mL) and THF (2.2 mL) was treatedwith 1-methylimidazole (23.8 μl, 0.29 mmole). The reaction mixture wasstirred at room temperature for 3 hrs. The reaction mixture waspartitioned between CH₂ Cl₂ and HCl solution (2N), and the aqueous phasewas separated and extracted with CH₂ Cl₂. The combined organic phase waswashed with HCl (2N), pH 7 phosphate buffer (0.4M), saturated NaCl soln.then dried over Na₂ SO₄ and evaporated to give the product (73.8 mg).

Step 2

7β-[2-(aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(3-methylimidazolium)-methyl]benzthiazol-2-yl-]thio-ceph-3-em-4-carboxylate

4'-Methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(3-methylimidazolium)-methyl]benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylateiodide (73.8 mg) was treated with anisole(0.77 mL) and TFA (2.5 mL). Thereaction was stirred at room temperature for 15 min. and worked up andpurified as described in example 5, step 4 to give the desired product(12.7 mg).

NMR: (D₂ O/CD₃ CN 2:1, 400 MHz) δ3.68 (d, J=16, S--CH₂); 4.04 (s, OCH₃);4.15 (s, CH₃ N⁺); 4.17 (d, J=16, S--CH₂); 5.54 (d, J=5, C-6 H); 5.68(s,ArCH₂ N⁺) 6.02 (d, J=5, C-7 H); 7β(s, Thiazolyl H); 7.5-7.7 (m. ArH);8.04 (s, Benzthiazolyl 4H); 8.17 (d, Benzthiazolyl 7H) 8.98 (s,imidazolium 2H).

EXAMPLE 9

7β-[2-(2-AMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-{5-[4-(2-HYDROXYETHYL)-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR261##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-[5-[4-(2-hydroxyethyl)-1,4-diazoniabicyclo[2.2.2](oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate)

Starting with the product of Example 5, Step 2 (64 mg) and following theprocedure of Example 4, Step 3, but substituting1-carbamoylmethyl-4-aza-1-azoniabicyclo[2.2.2]octanetrifluoromethylsulfonate, with1-(2-hydroxyethyl)-4-aza-1-azoniabicyclo[2.2.2]octanetrifluoromethylsulfonate one obtains the desired product (76.4 mg).

IR: λ^(max), cm⁻¹ ; 3478, 1789, 1731, 1681.

Step 2

7β-[2-(2-aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{5-[4-(2-hydroxyethyl)-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylate chloride

The product of Step 1 (76.4 mg) was treated under the conditions ofexample 5, step 4 to give the desired product (9.1 mg).

NMR:(D₂ O/CD₃ CN 10:1, 400 MHz) δ3.46 (d, J=16, S--CH₂); 3.60 (m, CH₂OH) 3.8-4.04 (m, OCH₃, N⁺ --CH₂ --CH₂ --N⁺, N⁺ --CH₂ --CH₂ OH); 479 (s,Ar--CH₂ --N⁺); 5.31 (d, J=5.5, C-6 H); 5.77 (d, J=5.5, C-7 H); 6.88 (s,Thiazolyl H); 7.42 (d, Benzthiazolyl 6H); 7.88 (s, Benzthiazolyl 4H);7.98 (d, Benzthiazolyl 7H).

EXAMPLE 10

7β-[2-(2-AMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-{[5-(3-AMINOPROPYL)-IMIDAZOLIUM)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATE##STR262##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(3-triphenylmethylaminopropyl)-imidazolium)-methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylateiodide

Starting with the product of Example 5, Step 2 (49 mg) and following theprocedure of example 8, step 1, but substituting 1-methylimidazole with1-(3-triphenylmethylaminopropyl)-imidazole, obtains the desired product(59 mg).

IR: λ^(max), cm⁻¹ ; 1783, 1731, 1681.

Step 2

7β-[2-(2-aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[5-(3-aminopropyl)-imidazolium)-methyl]benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylate

The product of Step 1 (59 mg) was treated under the conditions ofExample 5, Step 4 to give the desired product (6.2 mg).

NMR: (D₂ O, 500 MHz) δ2.21 (m, CH₂ --CH₂ --CH₂); 2.98 (t, CH₂ --NH₂)3.52 (d, J=18, S--CH₂); 3.96 (s, OCH₃); 3.97 (d, J=18, S--CH₂); 4.28 (t,N⁺ --CH₂ --CH₂); 537 (d, J=5, C-6 H); 5.49 (s, ArCH₂ N⁺); 5.84 (d, J=5,C-7H); 6.97(s, Thiazolyl H); 7.36 (d, Benzthiazolyl 6H); 7.53 (s,imidazolium 4 and 5H); 7.79 (s, Benzthiazolyl 4H); 7.91 (d,Benzthiazolyl 7H).

Mass Spec (ESI) M+1=686.

EXAMPLE 11

7β-[2-(AMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-{[4-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR263##

Step 1

4'-methoxybenzyl7β-phenylacetamido-3-(4-hydroxymethyl-(benzthiazol-2-yl)-thio-ceph-3-em-4-carboxylate

4'-Methoxybenzyl7β-phenylacetamido-3-trifluormethanesulfonyloxy-ceph-3-em-4-carboxylate(143.3 mg, 0.256 mmole) was suspended in methylene chloride (3.3 mL) andcooled to -10° C. In another flask sodium hydride (50% suspension inmineral oil, (12.3 mg, 0.256 mole) was suspended in THF (0.75 mL). Tothis was added 4-hydroxymethyl-2-mercaptobenzthiazole (50 mg, 0.253mmole) and the mixture stirred for 10 minutes at room temperature. Theresulting solution was added dropwise to the suspension of the triflatewith rapid stirring. The reaction was allowed to stir at -5° to 0° C.for 3 hrs. and then at room temperature for 0.5 hr and then treated withKH₂ PO₄ (0.5M solution, 1 mL), water (5 mL) and CH₂ Cl₂ (10 mL). Themixture was stirred at room temperature for 5 minutes. The two phaseswere separated and the organic phase was washed with water and saturatedNaCl solution and dried over Na₂ SO₄ and evaporated to give the crudeproduct. Crystallization from acetone gave the desired product (110.4mg).

NMR:(CDCl₃, 200 MHz) δ3.5 (d, J=20, S--CH₂); 3.66 (S, C₆ H₅ CH₂ ); 3.74(s, OCH₃); 3.83 (d, J=20, S--CH₂); 5.03 (s, ArCH₂ OH); 5.04 (d, J=5.5,C-6 H); 5.20 (s, CH₂ C₆ H₄ OCH₃); 5.9 (d of d, J=5.5, J=8, C-7 H); 6.21(d, J=8, NH); 6.7-8 (m, Ar H).

Step 2

4'-methoxybenzyl7β-phenylacetamido-3-(4-chloromethyl(benzthiazol-2-yl)-thio-ceph-3-em-4-carboxylate

The product from step 1 (110 mg) was suspended in CH₂ Cl₂ (3.3 mL) wascooled to 0° C. under N₂. Methanesulfonyl chloride (16 μl, 0.206 mmole)and Et₃ N (28 μl, 0.201 mmole) were added. After 0.5 hr TLC showedincomplete reaction. The reaction was warmed to room temperature andstirred for 70 minutes (no change by TLC). Another quantity of methanesulfonyl chloride (16 μl, 0.206 mmole) and Et₃ N (28 μl, 0.201 mmole)was added, and after 0.5 hours at room temperature, the reaction wasworked up by partitioning between CH₂ Cl₂ and water, drying the organicphase over Na₂ SO₄, and evaporating to dryness to give the mesylate (136mg).

IR: λ^(max), cm⁻¹ ; 1787, 1732, 1682.

The mesylate was dissolved in acetone (2.3 mL) and treated with LiCl(29.5 mg, 0.695 mmole) and the reaction allowed to stir at for 3 hrs.CH₂ Cl₂ (10 mL) was added and the precipitate was filtered off. Thefiltrate was evaporated to dryness. The residue was taken up in CH₂ Cl₂washed with water, dried and evaporated to give the product (105.5 mg).

NMR:(CDCl₃, 200 MHz) δ3.54 (d, J=18, S--CH₂); 3.65 (S, C₆ H₅ CH₂ ); 3.75(s, OCH₃); 3.98 (d, J=18,S--CH₂); 5.05 (s, ArCH₂ Cl); 5.04 (d, J=5.5,C-6 H); 5.23 (s, CH₂ C₆ H₄ OCH₃); 5.9 (d of d, J=5.5, J=8, C-7 H); 6.04(d, J=8, NH); 6.7-8 (m, Ar H).

Step 3

4'-methoxybenzyl7β-ammonium-3-(4-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylatep-toluenesulfonate

4'-Methoxybenzyl7β-phenylacetamido-3-(4-chloromethyl-(benzthiazol-2-yl)-thio-ceph-3-em-4-carboxylate(105 mg) was treated according to the procedure of example 4. Afteraddition of the p-toluenesulfonic acid, ether was added to the reactionmixture and the precipitated solid was filtered off and washed withether to give the product (69.3 mg). Cooling the filtrate and washingsgave a further 33.1 mg of product.

Step 4

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyiminolacetamido-3-(4-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

The product from Step 3 (102 mg) was treated under the conditions ofExample 4, Step 1 to give the desired product (46.9 mg, 47%) afterpreparative TLC purification.

NMR:(CDCl₃, 200 MHz) δ3.59 (d, J=16, S--CH₂); 3.76 (s, ArOCH₃); 4.02 (d,J-16, S--CH₂); 4.07(s, OCH₃); 5.06(ABq, ArCH₂ Cl); 5.17 (d, J=5.5, C-6H); 5.29 (s, CH₂ C₆ H₄ OCH₃); 6.0 (d of d, J-5.5, J=8, C-7 H); 6.6-8 (m,Ar H and NH).

IR: λ^(max), cm⁻¹ ; 1783, 1735, 1678.

Step 5

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-(4-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

The product from Step 4 was treated according to the procedure ofExample 5, Step 2, to give the desired product.

NMR:(CDCl₃, 200 MHz) δ3.65 (d, J=16, S--CH₂); 3.76 (s, OCH₃); 4.07(s,OCH₃); 4.2 (d, J=16, S--CH₂); 4.91(ABq, ArCH₂ I); 5.21 (d, J=5.5, C-6H); 5.3 (s, CH₂ C₆ H₄ OCH₃); 6.0 (d of d, J=5.5, J=8, C-7 H); 6.6-8 (m,Ar H and NH).

IR: λ^(max), cm⁻¹ ; 1787, 1732, 1681.

Step6

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[4-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate)

The product from Step 5 (26 mg, 0.247 mmole)was treated according to theconditions of Example 4, Step 3 to give the desired product (35 mg).

IR: λ^(max), cm⁻¹ ; 1790, 1733, 1697.

Step 7

7β-[2-(aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[4-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatechloride

The product from Step 6 (35 mg) was treated according to the conditionsof Example 5, Step 4, to give the desired product (3.4 mg).

NMR:(D₂ O, 500 MHz) δ3.61 (d, J=16, S--CH₂); 3.94 (d, J=16, S--CH₂);3.98 (s, OCH₃); 4.0 and 4.1 (2m, N⁺ --CH₂ --CH₂ --N⁺); 5.09 (ABq, ArCH₂--N⁺); 5.35 (d, J=5.5, C-6 H); 5.68 (d, J=5.5, C-7 H); 7.04 (s,Thiazolyl H); 7.47 (t, Benzthiazolyl 6H); 7.58 (d, Benzthiazolyl 4H);8.08 (d, Benzthiazolyl 7H).

EXAMPLE 12

7β-[2-(AMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-{[6-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR264##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-(6-hydroxymethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

Sodium hydride (50% suspension in oil, 4.8 mg, 0.1 mmole was suspendedin THF (0.3 mL) at under N₂, was added6-hydroxymethyl-2-mercaptobenzthiazole (20.3 mg, 0.103 mmole). Thereaction mixture was stirred for 10 min. then cooled to -60° C. and4'-methoxybenzyl7β-[2-(aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-trifluormethanesulfonyloxy-ceph-3-em-4-carboxylate(89.3 mg, 0.099 mmole) from Example 5 in CH₂ Cl₂ (1.3 mL) was added. Thereaction temp was raised to -20° C. and the mixture stirred at -20 to-15° C. for 50 min. Work up as described in Example 11, Step 1, gave theproduct (90.1 mg) as a mixture of Δ³ and Δ² isomers (7:3 ratio).

Step 2

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-(6-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

The product from step 4 of Example 11 (90 mg) in CH₂ Cl₂ (1.7 mL),cooled to 0° C. under N₂, was treated with MsCl (13 μl, 0.168 mmole) andEt₃ N (22 μl, 0.158 mole). After 45 minutes, additional portions of MsCl(6 μl, 0.0775 mmole) and Et₃ N (11 μl, 0.078 mmole) were added and thereaction was worked up after a total of 1.25 hr as described in example13, step 2 to give the mesylate (101.4 mg).

The mesylate was dissolved in acetone (1.8 mL) and treated with KI (84mg, 0.506 mmole) and the reaction allowed to stir at room temperaturefor 2 hrs. The solvent was removed under reduced pressure and theresidue was taken up in CH₂ Cl₂ and filtered and the filtrate wasevaporated to give the product (95.9 mg) as a mixture of Δ³ and Δ²isomers.

Step 3

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[6-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethylsulfonate)

The product from Step 2 (95 mg) was treated according to the conditionsof Example 4, Step 3 to give the desired product (129.5 mg).

Step4

7β-[2-(aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{[6-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl) methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatechloride

The product from Step 3 (129.5 mg) was treated according to theconditions of Example 5, Step 4 to give the desired product (6.0 mg) andthe Δ² isomer (3.5 mg).

NMR:(D₂ O/CD₃ CN 2/1, 400 MHz) δ3.85 (d, J=16, S--CH₂); 3.94 (d, J=16,S--CH₂); 3.98 (s, OCH₃); 4.28 and 4.45 (2m, N⁺ --CH₂ --CH₂ --N⁺); 4.6(s, CO--CH₂ --N⁺); 5.16 (s, Ar--CH₂ --N⁺); 5.64 (d, J=5.5, C-6 H); 6.15(d, J=5.5, C-7 H); 7.22 (s, Thiazolyl H); 7.9 (d, Benzthiazolyl 6H);8.48 (d, Benzthiazolyl 4H); 8.42 (s, Benzthiazolyl 7H).

EXAMPLE 13

7β-[2-(AMINOTHIAZOL-4-YL)-2-Z-METHOXYIMINO]ACETAMIDO-3-{4-[4-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2]OCT-1-YL)-METHYLPHENYL]-THIAZOL-2-YL}-THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR265##

Step 1

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyiminolacetamido-3-[4-(4-hydroxymethylphenyl)-thiazol-2-yl]thio-ceph-3-em-4-carboxylate

Sodium hydride (50% suspension in oil, 4.8 mg, 0.1 mmole) was suspendedin THF (0.3 mL) at room temperature under N₂, was added4-(4-hydroxymethylphenyl)-2-mercaptothiazole (23 mg, 0.103 mmole). Thereaction mixture was stirred at room temperature for 10 min. then addedto a solution of 4'-methoxybenzyl7β-[2-(aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-trifluormethanesulfonyloxy-ceph-3-em-4-carboxylate(64 mg, 0.0716 mmole) from example 3, in CH₂ Cl₂ (1.3 mL), cooled to 0°C. under N₂. The reaction mixture was stirred at 0° C. for 35 min. Workup as described in example 11, step 1 gave the product (88 mg).

NMR:(CDCl₃, 200 MHz) δ3.50 (d, J=18, S--CH₂); 3.72 (d, J=18, S--CH₂);3.77 (s, OCH₃); 4.03 (s, OCH₃); 4.74 (s, ArCH₂ OH; 5.08 (d, J=5.5, C-6H); 5.27 (s, CH₂ C₆ H₄ OCH₃); 5.93 (d of d, J=5.5, J=8, C-7 H); 6.6-7.9(m, Ar H and NH).

IR: λ^(max), cm⁻¹ ; 3675, 1784, 1727, 1678.

Step 2

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-[4-(4-iodomethylphenyl)-thiazol-2-yl-thio-ceph-3-em-4-carboxylate

The product from Step 1 (88 mg) was treated under the conditions ofExample 12, Step 2, to give the desired product (82 mg).

NMR:(CDCl₃, 200 MHz) δ3.50 (d, J=18, S--CH₂); 3.77 (s, OCH₃); 4.07 (s,OCH₃); 4.48 (s, ArCH₂ I; 5.08 (d, J=5.5, C-6 H); 5.25 (s, CH₂ C₆ H₄OCH₃); 5.93 (d of d, J=5.5, J=8, C-7 H); 6.6-7.9 (m, Ar H and NH).

IR: λ^(max), cm⁻¹ ; 1781, 1727, 1678.

Step 3

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{4-[4-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2]oct-1-yl)-methylphenyl]-thiazol-2-yl}thio-ceph-3-em-4-carboxylatebis (trifluoromethanesulfonate)

The product from Step 2 (82 mg) was treated according to the conditionsof Example 4, Step 3 to give the desired product (94.8 mg).

Step 4

7β-[2-(aminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-{4-[4-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2]oct-1-yl)methylphenyl]-thiazol-2-yl}-thio-ceph-3-em-4-carboxylatechloride

The product from Step 3 (94.8 mg)was treated according to the conditionsof Example 5, Step 4, to give the desired product (5.7 mg).

NMR:(D₂ O, 500 MHz) δ3.48 (d, J=17, S--CH₂); 3.83 (d, J=17, S--CH₂);3.74 (s, OCH₃); 4.02 and 4.21 (2m, N⁺ --CH₂ --CH₂ --N⁺); 4.34 (s,CO--CH₂ N⁺); 4.78 (s, Ar--CH₂ --N⁺); 5.28 (d, J=5.0, C-6 H); 5.77 (d,J=5.0, C-7 H); 6.74 (s, Thiazolyl H); 7.5 (d, Phenyl H); 7.84 (d, PhenylH); 7.82 (s, Phenylthiazolyl H).

EXAMPLE 14

7β-[2-(AMINOTHIAZOL-4-YL)-2-(Z-METHOXYIMINO]ACETAMIDO-3-[4-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2]-OCT-1-YL)-METHYL-1,3THIAZOLO[5,4-B]THIOPHENE-2-YL]-THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR266## Step 1 4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-(Z-methoxyimino]acetamido-3-[4-hydroxymethyl-1,3-thiazolo-(5,4-b)-thiophene-2-yl]-thio-ceph-3-em-4-carboxylate

To sodium hydride (60% suspension in oil, 8 mg, 0.2 mmole) suspended inTHF (0.5 mL) at room temperature under N₂, was added2-mercapto-4-hydroxymethyl-1,3-thiazolo[5,4-b]thiophene (40.6 mg, 0.2mmole). The reaction mixture was stirred at room temperature for 15minutes, then 0.26 mL of this solution was added to a solution of4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-Z-methoxyimino]acetamido-3-trifluormethanesulfonyloxy-ceph-3-em-4-carboxylate(85 mg, 0.1 mmole) from example 5, in CH₂ Cl₂ (2.5 mL), cooled to -15°C. under N₂. The reaction mixture was stirred at -15° C. for 45 minutes.Work up as described in example 13, step 1, gave the product (54 mg).

NMR: (CDCl₃, 200 MHz) δ3.45 (d, J=18, S--CH₂); 3.62 (d, J=18, S--CH₂);3.77 (s, OCH₃); 4.03 (s, OCH₃); 4.94 (s, ArCH₂ OH; 5.06 (d, J=5.5, C-6H); 5.27 (s, CH₂ C₆ H₄ OCH₃); 5.93 (d of d, J=5.5, J=8, C-7 H); 6.6-7.5(m, Ar H and NH).

IR: λ^(max), cm⁻¹ ; 3298, 1780, 1729, 1681.

Step 2

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-(Z-methoxyimino)acetamido-3-[4-iodomethyl-1,3-thiazolo-(5,4-b)-thiophene-2-yl]-thio-ceph-3-em-4-carboxylate

The product from Step 1 (54 mg) was treated under the conditions ofExample 12, Step 2 to give the desired product (56 mg).

NMR:(CDCl₃, 200 MHz) δ3.51 (d, J=18, S--CH₂); 3.79 (s, OCH₃); 4.05 (s,OCH₃); 4.64 (s, ARCH_(21;) 5.1 (d, J=5.0, C-6 H); 5.28 (s, CH₂ C₆ H₄OCH₃); 5.93 (d of d, J=5.0, J=8, C-7 H); 6.6-7.5 (m, Ar H and NH).

IR: λ^(max), cm⁻¹ ;3305, 1782, 1732, 1682.

Step 3

4'-methoxybenzyl7β-[2-(triphenylmethylaminothiazol-4-yl)-2-(Z-methoxyimino)acetamido-3-[4-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2]-oct-1-yl)-methyl-1,3-thiazolo[5,4-b]thiophene-2-yl]-thio-ceph-3-em-4-carboxylatebis (trifluoromethanesulfonate)

The product from Step 2 (56 mg)was treated according to the conditionsof Example 4, Step 3 to give the desired product.

Step 4

7β-[2-(aminothiazol-4-yl)-2-(Z-methoxyimino)acetamido-3-[4-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2]-oct-1-yl)-methyl-1,3-thiazolo[5,4-b]thiophene-2-yl]-thio-ceph-3-em-4-carboxylatechloride

The product from Step 3 was treated according to the conditions ofExample 5, Step 4, to give the desired product (8.5 mg).

NMR:(D₂ O, 500 MHz) δ3.50 (d, J=17, S--CH₂); 3.88 (d, J=17, S--CH₂);3.95 (s, OCH₃); 4.07 and 4.19 (2m, N⁺ --CH₂ --CH₂ --N⁺); 4.34 (s,CO--CH₂ N⁺); 4.93 (s, Ar--CH₂ --N⁺); 5.31 (d, J=5.0, C-6 H); 5.79 (d,J=5.0, C-7 H); 6.97 (s, Thiazolyl H); 8.02(s, Thiazolothiophene H).

EXAMPLE 15

7β-[2-(5-AMINO-1,2,4-THIADIAZOL-3-YL)-(2-Z-2-METHOXYIMINO)]ACETAMIDO-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR267##

Step 1

4'-methoxybenzyl7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyimino]acetamido-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

4'-Methoxybenzyl7β-ammonium-3-(5-chloromethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylatep-toluenesulfonate (70 mg, 0.1 mmole) was taken up in CH₂ Cl₂, andcooled to -10° C. under N₂.2-(5-amino-1,2,4-thiadiazol-3-yl)-(2-Z-2-methoxyimino)]acetyl chloride(24 mg, 0.11 mmole) was added followed by pyridine (16 μl, 0.22 mmole).The reaction mixture was stirred at -10° C. for 0.5 hr. The reactionmixture was diluted with EtOAc and washed with water, dried over MgSO₄and evaporated to give the crude product (56 mg).

NMR: (CD₃ CN/CDCl₃, 500 MHz) δ3.60 (d, J=18, S--CH₂); 3.69 (s, OCH₃);3.93 (d, J=18, S--CH₂); 4.02 (s, OCH₃); 4.76(s, ArCH₂ Cl); 5.18 (s, CH₂C₆ H₄ OCH₃); 5.24 (d, J=5.0, C-6 H); 5.97 (d of d, J=5.0, J=8, C-7 H);6.6-8.8 (m, Ar H and NH).

Step 2

4'-methoxybenzyl7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyimino]acetamido-3-(5-iodomethyl-2-benzthiazolylthio)-ceph-3-em-4-carboxylate

The product from Step 1 (56 mg) was treated under the conditions ofExample 5, Step 2 to give the desired product (58 mg).

NMR:(CD₃ CN/CDCl₃, 2/1, 500 MHz) δ3.59 (d, J=18, S--CH₂); 3.69 (s,OCH₃); 3.93 (d, J=18, S--CH₂); 4.02 (s, OCH₃); 4.65 (s, ArCH₂ I); 5.17(s, CH₂ C₆ H₄ OCH₃); 5.24 (d, J=5.0, C-6 H); 5.96 (d of d, J=5.0, J=8,C-7 H); 6.6-8.8 (m, Ar H and NH).

Step 3

4'-methoxybenzyl7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-Z-methoxyimino]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatebis (trifluoromethanesulfonate)

The product from Step 2 (58 mg) was treated under the conditions ofExample 5, Step 3 to give the desired product (77 mg).

Step 4

7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(2-Z-2-methoxyimino)]acetamido-3-{[5-(4-carbamoylmethyl-1,4-diazoniabicyclo[2.2.2])oct-1-yl)methyl]-benzthiazol-2-yl-}thio-ceph-3-em-4-carboxylatechloride

The product from Step 3 (77 mg) was treated under the conditions ofExample 5, Step 4 to give the desired product (10.2 mg).

NMR:(D₂ O/CD₃ CN, 5/1, 500 MHz) δ3.62 (d, J=17, S--CH₂); 4.12 (s, OCH₃);4.08 and 4.25 (2m, N⁺ --CH₂ --CH₂ --N⁺); 4.4 (s, CO--CH₂ --N⁺); 4.94 (s,Ar--CH₂ --N⁺); 5.45 (d, J=5.0, C-6 H); 5.95 (d, J=5.0, C-7 H); 7.54 (d,Benzthiazolyl 6H); 7.99 (s, Benzthiazolyl 4H); 8.15 (d, Benzthiazolyl7H).

EXAMPLE 16

7β-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-3-tert-BUTYLMETHYLACRYLAMIDO]-[-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR268##

Substitution of(Z)-2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino)-aceticacid hydrochloride by(Z)-2-(2-triphenylmethylaminothiazol-4-yl)-3-tert-butylmethylacrylicacid in the procedure of example 4, step 1, followed by the procedure ofsteps 2 to 4 gives the desired product.

EXAMPLE 17

7β-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-3CYCLOPENTYLMETHYLACRYLAMIDO]-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR269##

Substitution of(Z)-2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino)-aceticacid hydrochloride by(Z)-2-(2-tritylaminothiazol-4-yl)-3-cyclopentylmethylacrylic acid in theprocedure of example 4, step 1, followed by the procedure of steps 2 to4 gives the desired product.

EXAMPLE 18

7β-[(Z)-2-(2-AMINOTHIAZOL-4-YL)-3-CYCLOHEXYLACRYLAMIDO]-3-{[5-(4-CARBAMOYLMETHYL-1,4-DIAZONIABICYCLO[2.2.2])OCT-1-YL)METHYL]-BENZTHIAZOL-2-YL-}THIO-CEPH-3-EM-4-CARBOXYLATECHLORIDE ##STR270##

Substitution of(Z)-2-(triphenylmethylaminothiazol-4-yl)-2-Z-2-fluoroethoxyimino)-aceticacid hydrochloride by((Z)-2-(2-tritylaminothiazol-4-yl)-3-cyclohexylacrylic acid in theprocedure of example 4, step 1, followed by the procedure of steps 2 to4 gives the desired product.

What is claimed is:
 1. A compound represented by the formula I:##STR271## or a pharmaceutically acceptable salt or solvate thereof,wherein: Y' represents CH or N;M represents hydrogen, a negative charge,a biolabile ester forming group or a carboxyl protecting group; R¹³represents R¹ or N(R¹)₂ ; W⁻ is present or absent, and when present,represents a negatively charged counterion; Z' represents (a) CR^(y')R^(z') wherein R^(y') and R^(z') independently represent H, C₁₋₆ alkylor C₃₋₈ cycloalkyl, each optionally substituted with 1-3 groups selectedfrom R^(e'), or (b) N substituted with OR₁ with R¹ equal to H, C₁₋₆alkyl or C₁₋₆ alkyl substituted with from 1-3 groups selected fromR^(e') ; C₃₋₈ cycloalkyl; C₃₋₈ cycloalkenyl; C₃₋₈ cycloalkyl substitutedwith 1-3 groups selected from R^(e'), or C₃₋₈ cycloalkenyl substitutedwith 1-3 groups selected from R^(e') ; R^(e') represents a memberselected from the group consisting of:a) --CF₃ ; b) a halogen atomselected from the group consisting of --Br, --Cl, --F and --I; c)--OC₁₋₄ alkyl, Wherein the alkyl portion thereof is optionallysubstituted by 1-3 groups selected from R^(q). R^(q) is selected fromthe group consisting of hydroxy, methoxy, cyano, --C(O)NH₂, --C(O)NHC₁₋₄alkyl, --C(O)N(C₁₋₄ alkyl)₂, --OC(O)NH₂, --CHO, --OC(O)NHC₁₋₄ alkyl,OC(O)N(C₁₋₄ alkyl)₂, --SO₂ NH₂,--SO₂ N(C₁₋₄ alkyl)₂, --S(O)C₁₋₄alkyl,--SO₂ C₁₋₄ alkyl, --F,--CF₃, --SO₃ M^(b) with M^(b) representing Hor an alkali metal, and --CO₂ M^(a), where M^(a) is H, alkali metal,methyl or phenyl; tetrazolyl (where the point of attachment is thecarbon atom of the tetrazole ring and one of the nitrogen atoms isoptionally substituted by 1-3 of the other R^(q) groups as definedabove); d) --OH: e) --OC(O)R^(s), where R^(s) is C₁₋₄ alkyl or phenyl,each of which is optionally substituted by 1-3 groups R^(q) as definedabove; f) --OC(O)N(R^(y"))r^(z"), where R^(y") and R^(z") areindependently H, C₁₋₄ alkyl, (optionally substituted by 1-3 R^(q) groupsas defined above), or are taken together to represent a 3- to 5-memberedalkylidene radical which forms a ring (optionally substituted with R^(q)as defined above), or a 2- to 4-membered alkylidene radical interruptedby --O--, --S--, --S(O)-- or --S(O)₂ --which forms a ring, said ringbeing optionally substituted with. 1-3 groups R^(q) as defined above; g)--S(O)_(n) --R^(s), where n=0-2, and R^(s) is defined above; h) --SO₂N(R^(y"))R^(z"), where R^(y") and R^(z") are as defined above; i) --N₃ ;j) --NR^(x).sub.(0-1) R^(y) R^(z) wherein R^(x), R^(y) and R^(z)independently represent H, C₁₋₄ alkyl or C₁₋₄ alkyl substituted withfrom 1-3 R^(q) groups, or R^(x), R^(y) and R^(z) are taken together torepresent either a 3- to 7-membered heterocyclic or heteroaryl ring,optionally substituted with 1-3 R^(q) groups, or a 2- to 4- memberedalkylidene radical interrupted by N, O or S(O)_(x) with x equal to 0, 1or 2, to form a ring, said alkylidene being optionally substituted withfrom 1 to 3 R^(q) groups, such that when R^(x), R^(y) and R^(z) arepresent, NR^(x) R^(y) R^(z) is a quaternary nitrogen containing groupwhich may be part of a ring, or R^(x), R^(y) and R^(z) are taken incombination to represent a C₄ to C₁₀ alkanetriyl group, optionallysubstituted with 1-3 R^(q) groups, said alkanetriyl group beingoptionally interrupted with 1-3 heteroatoms selected from N⁺ R^(t), Oand S(O)_(x) with x and R^(t) as defined above;k) --N(R^(t))C(O)H, whereR^(t) is H or C₁₋₄ alkyl, said alkyl group being optionally substitutedwith 1-3 groups R^(q) as defined above; l) --N(R^(t))C(O)C₁₋₄ alkyl,wherein R^(t) is as defined above; m) --N(R^(t))C(O)OC₁₋₄ alkyl, whereinR^(t) is as defined above; n) --N(R^(t))C(O)N(R^(y))R^(z) where R^(t),R^(y) and R^(z) are defined above; o) --N(R^(t))SO₂ R^(s), where R^(s)and R^(t) are as defined above; p) --CN; q) a formyl or acetalizedformyl radical which is --C(O)H or --CH(OCH₃)₂ ; r) --C(OCH₃)₂ C₁₋₄alkyl, where the alkyl is optionally substituted by 1-3 groups R^(q) asdefined above; s) --C(O)R^(s), where R^(s) is as defined above; t)--(C═NOR^(z"))R^(y") where R^(y") and r^(z") are as defined above,except they may not be joined together to form a ring; u) --C(O)OC₁₋₄alkyl, where-the alkyl is optionally substituted by 1-3 groups R^(q) asdefined above; v) --C(O)N(R^(y"))R^(z"), where R^(y") and R^(z") are asdefined above; w) --C(O)N(OR^(y"))r^(z"), where R^(y") and R^(z") are asdefined above, except they may not be joined together to form a ring; x)--C(S)N(R^(y"))r^(z") where R^(y") and R^(z") are as defined above; y)--COOM^(a) where M^(a) represents H, C₁₋₄ alkyl, phenyl or an alkalimetal; z) --SCN; as) --SCF₃ ; ab) tetrazolyl, where the point ofattachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is substituted by hydrogen, an alkali metal or a C t-4alkyl optionally substituted by R^(q) as defined above; ac) an anionicfunction which is selected from the group consisting of: P=O(OM^(a))₂ ;P=O(OM^(a))--[O(C₁₋₄ alkyl)]; P=O(OM^(a))--(C₁₋₄ alkyl);P=O(OM^(a))N(R^(y"))r^(z") ; P=O(OM^(a))NHR^(x') ; SO₂ M^(a) ; SO₃ M^(a); SO₂ NM^(a) CON(R^(y"))R^(z"), and SO₂ NM^(a) CN, where R^(x') isphenyl or heteroaryl, said heteroaryl group being a monocyclic, aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, one of the carbon atoms has been replaced by anitrogen atom, one carbon atom is optionally replaced by a heteroatomselected from O or S, and from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms, and where the phenyl andheteroaryl are optionally substituted by 1-3 groups R^(q), said R^(q),M^(a), R^(y") and R^(z") are as defined above; ad) a C₃₋₇ cycloalkylgroup; ae) a C₅₋₇ cycloalkyl group in which one of the carbon atoms inthe ring is replaced by a heteroatom selected from O, S, NH, or N(C₁₋₄alkyl) and in which one additional carbon may be replaced by the NH orN(C₁₋₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring; af) a C₂₋₄ alkenyl radical,optionally substituted by 1-3 of the substituents a) to ac) above andphenyl which is optionally substituted by R^(q) as defined above; ag) aC₂₋₄ alkynyl radical, optionally substituted by 1-3 of the substituentsa) to ac) above; ah) a C₁₋₄ alkyl radical; ai) a C₁₋₄ alkyl groupsubstituted by 1-3 of the substituents a)-aa) above; aj) a C₁₋₄ alkylradical substituted with 1-3 groups selected from aryl, oxime,heteroaryl, C₃₋₇ cycloalkyl and heterocycloalkyl, each of which isunsubstituted or substituted with 1 to 3 R^(q) groups; ak) a C₃₋₇cycloalkyl radical substituted with 1-3 of the substituents a)-aa)above; al) a C₃₋₇ heterocycloalkyl radical substituted with 1-3 of thesubstituents a)-aa) above; am) a C₆₋₁₀ aryl radical; an) a C₆₋₁₀ arylradical substituted with 1-3 of the substituents a)-aa) above; ao) a6-10 membered heteroaryl radical; and ap) a 6-10 membered heteroarylradical substituted with 1-3 of the substituents a)-aa) above;##STR272## represents a heterocyclic group with from one to threepositively charged atoms, and is selected from the group consisting of:##STR273## wherein: ##STR274## represents the point of attachment to S;A, B, C, D, X and Y independently represent C or N; Z represents C, O, Sor N, such that at least one of A, B, C, D, X and Y represents N, or Zrepresents O, S or N; one R^(e) represents --R* and the others representH, R^(e') or R^(f) ; --R* represents one of the groups (a) through (c):##STR275## when --R* represents (a) ##STR276## E represents --(CR³R⁴)_(r) --Q--(CR³ R⁴)_(s) wherein r is 0-6, s is 1-6; Q represents amember selected from the group consisting of: a covalent bond, --O--,--S(O)_(x) -- with x equal to 0, 1 or 2, --NR³ --, --SO₂ NR³ --, --NR³SO₂ --, --C(O)NR³ --, --NR³ C(O)--, --CR3═CR⁴ --, --C(O)--, --OC(O)--,--(O)CO--, ##STR277## in which R³ and R⁴ independently represent H orC₁₋₄ lower alkyl, and (CR³ R⁴)_(s) -- is attached to the ring nitrogen;##STR278## represents a 5 or 6 membered monocyclic heterocycle or an8-10 membered bicyclic heterocycle, bonded to E through the ringnitrogen and having a substituent group R^(f) optionally attached to thering nitrogen, and having 0-3 R^(e') groups attached to other atoms ofthe heterocyclic group, said ring nitrogen being tertiary or quaternaryby virtue of E, the ring bonds and the optional R^(f) which may beattached, said heterocyclic group being aromatic, partially aromatic ornon-aromati, said heterocycle further containing 0-3 additional nitrogenatoms and 0-1 oxygen or sulfur atom; each R^(f) independently representshydrogen, --NH₂, --O--, --C₁₋₄ alkyl, optionally substituted with 1-3groups selected from R^(q) ; --C₃₋₇ cycloalkyl, optionally substitutedwith 1-3 groups selected from R^(q) ; --C₅₋₇ cycloalkyl group in whichone of the carbon atoms in the ring is replaced by a heteroatom selectedfrom O, S, NH, or N(C₁₋₄ alkyl) and in which one additional carbon maybe replaced by the NH or N(C₁₋₄ alkyl), and in which at least one carbonatom adjacent to each nitrogen heteroatom has both of its attachedhydrogen atoms replaced by one oxygen thus forming a carbonyl moiety andthere are one or two carbonyl moieties present in the ring; a C₂₋₄alkenyl radical, optionally substituted by 1-3 substituents selectedfrom R^(q) ; a C₂₋₄ alkynyl radical, optionally substituted by 1-3substituents selected from R^(q) ; a C₁₋₄ alkyl radical substituted with1-3 groups selected from aryl, oxime, heteroaryl, C₃₋₇ cycloalkyl andheterocycloalkyl, each of which is unsubstituted or substituted with 1to 3 groups selected from R^(q) ; a C₃₋₇ cycloalkyl radical optionallysubstituted with 1-3 substituents selected from R^(q) ; a C₆₋₁₀ arylradical, optionally substituted with 1-3 substituents selected fromR^(q) ; and a 6-10 membered heteroaryl group, optionally substitutedwith 1-3 substituents selected from R^(q) ; when --R * represents##STR279## E' represents --(CR³ R⁴)_(m') --Q--(CR³ R⁴)_(m') -- with eachm' independently equal to 0-6, and Q, R³ and R⁴ as defined above, exceptthat when each m' is
 0. Q is not a covalent bond, and --(CR³ R⁴)_(m')attached to the heterocyclic ring; ##STR280## represents a 5 or 6membered monocyclic heterocycle or an 8-10 membered bicyclicheterocycle, said heterocycle being aromatic, partially aromatic ornon-aromatic, bonded to E' through an atom other than the ring nitrogen,and having 0-2 R^(f) groups attached to the ring nitrogen, said nitrogenin the heterocycle being tertiary or quaternary by virtue of the ringbonds and the optional R^(f) groups which may be attached, saidheterocycle further containing 0-1 oxygen or sulfur atom and 0-2additional nitrogen atoms therein; R^(e') and R^(f) are as definedabove; when --R* represents

    E.sub.p --N.sup.+ R.sup.10 R.sup.11 R.sup.12 (014 1),      (c)

E is as defined above and p is an integer 0 or 1; R¹⁰, R¹¹ and whenpresent, R¹², are independently H, C₁₋₄ alkyl or C₁₋₄ alkyl substitutedwith 1-3 R^(q) groups; or R¹⁰ and R¹¹ may be taken together to representa C₃ -C₅ alkylidene radical to form a ring (optionally substituted with1-3 R^(q) groups as defined below), uninterrupted or interrupted by O,S, S(O), SO₂, N(O)R^(e') or N⁺ (R^(e'))₁₋₂, where R^(e') is aspreviously defined, or R¹⁰, R¹¹ and R¹² may be taken in Combination torepresent a C₄ to C₁₀ alkanetriyl group, optionally substituted with 1-3R^(e') groups, said alkanetriyl group being optionally interrupted with1-3 heteroatoms selected from N⁺ R^(e'), N⁺ R^(f), O and S(O)_(x) withx, R^(e') and R^(f) as defined above.
 2. A compound in accordance withclaim 1 wherein Y' represents N.
 3. A compound in accordance with claim1 wherein Y' represents C.
 4. A compound in accordance with claim 3wherein X represents a nitrogen atom.
 5. A compound in accordance withclaim 1 wherein A, B, C and D represent carbon atoms.
 6. A compound inaccordance with claim 5 wherein 1-2 of A, B, C and D represent anitrogen atom.
 7. A compound in accordance with claim 1 whereinrepresents nitrogen and Z represents sulfur.
 8. A compound in accordancewith claim 1 wherein X represents a nitrogen atom, and Y and Z representcarbon.
 9. A compound in accordance with claim 5 wherein X representsnitrogen and Z represents sulfur.
 10. A compound in accordance withclaim 1 wherein--R* represents (a) ##STR281##
 11. A compound inaccordance with claim 1 wherein --R* represents (b) ##STR282##
 12. Acompound in accordance with claim 1 wherein --R* represents (c) --E_(p)--N⁺ R¹⁰ R¹¹ R¹² (0-1).
 13. A compound in accordance with claim 1wherein Het represents ##STR283##
 14. A compound in accordance withclaim 1 wherein R¹ and HET are selected in accordance with the followingtable:

                                      TABLE I                                     __________________________________________________________________________     ##STR284##                                                                    ##STR285##                                                                              ##STR286##                                                         __________________________________________________________________________    75                                                                              CH.sub.2 CH.sub.2 F                                                                    ##STR287##                                                         76                                                                              CH.sub.2 CH.sub.2 F                                                                    ##STR288##                                                         __________________________________________________________________________


15. A compound in accordance with claim 1 wherein R¹ and HET areselected in accordance with the following table:

                                      TABLE II                                    __________________________________________________________________________     ##STR289##                                                                    ##STR290##                                                                              ##STR291##                                                         __________________________________________________________________________    75                                                                              CH.sub.2 CH.sub.2 F                                                                    ##STR292##                                                         76                                                                              CH.sub.2 CH.sub.2 F                                                                    ##STR293##                                                         __________________________________________________________________________


16. A pharmaceutical composition comprised of a compound as described inclaim 1 in combination with a pharmaceutically acceptable carrier.
 17. Amethod of treating a bacterial infection in a mammalian patient in needof such treatment, comprising administering to said patient a compoundas described in claim 1 in an amount effective to treat said bacterialinfection.